Non-imidazole aryloxyalkylamines

ABSTRACT

Substituted aryloxyalkylamines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

FIELD OF THE INVENTION

The present invention relates to aryloxyalkylamines, their synthesis andtheir use, for example, for the treatment of disorders and conditionsmediated by the histamine receptor.

BACKGROUND OF THE INVENTION

Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance.Histamine exerts a physiological effect via multiple distinct G-proteincoupled receptors. It plays a role in immediate hypersensitivityreactions and is released from mast cells following antigen IgE antibodyinteraction. The actions of released histamine on the vasculature andsmooth muscle system account for the symptoms of the allergic response.These actions occur at the H₁ receptor (Ash, A. S. F. and Schild, H. O.,Br. J. Pharmacol., 1966, 27, 427) and are blocked by the classicalantihistamines (e.g. diphenhydramine). Histamine is also an importantregulator of gastric acid secretion through its action on parietalcells. These effects of histamine are mediated via the H₂ receptor(Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R. andParsons, E. M., Nature, 1972, 236, 385) and are blocked by H₂ receptorantagonists (e.g. cimetidine). The third histamine receptor —H₃— wasfirst described as a presynaptic autoreceptor in the central nervoussystem (CNS) (Arrang, J.-M., Garbarg, M., and Schwartz, J.-C., Nature1983, 302, 832) controlling the synthesis and release of histamine.Recent evidence has emerged showing that the H₃ receptors are alsolocated presynaptically as heteroreceptors on serotonergic,noradrenergic, dopaminergic, cholinergic, and GABAergic(gamma-aminobutyric acid containing) neurons. These H₃ receptors havealso recently been identified in peripheral tissues such as vascularsmooth muscle. Consequently there are many potential therapeuticapplications for histamine H₃ agonists, antagonists, and inverseagonists. (See: “The Histamine H ₃ Receptor—A Target for New Drugs”,Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998; Morisset etal., Nature, 2000, 408, 860-864.) A fourth histamine receptor —H₄— wasrecently described by Oda et al., (J. Biol. Chem., 2000, 275,36781-36786).

The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin etal, Br. Res., 1990, 523, 325; Monti et al Eur. J. Pharmacol., 1991, 205,283). Their use in the treatment of migraine has also been suggested(McLeod et al Abstr. Society Neuroscience, 1996, 22, 2010) based ontheir ability to inhibit neurogenic inflammation. Other applicationscould be a protective role in myocardial ischemia and hypertension whereblockade of norepinephrine release is beneficial (Imamura et al J.Pharmacol. Expt. Ther., 1994, 271, 1259). It has been suggested thathistamine H₃ agonists may be beneficial in asthma due to their abilityto reduce non-adrenergic non-cholinergic (NANC) neurotransmission inairways and to reduce microvascular leakage (Ichinose et al Eur. J.Pharmacol., 1989, 174, 49).

Several indications for histamine H₃ antagonists and inverse agonistshave similarly been proposed based on animal pharmacology experimentswith known histamine H₃ antagonists (e.g. thioperamide). These includedementia, Alzheimer's disease (Panula et al Abstr. Society Neuroscience,1995, 21, 1977), epilepsy (Yokoyama et al Eur. J. Pharmacol., 1993, 234,129) narcolepsy, eating disorders (Machidori et al Brain Research 1992,590, 180), motion sickness, vertigo, attention deficit hyperactivitydisorders (ADHD), learning and memory (Barnes et al Abstr. SocietyNeuroscience, 1993, 19, 1813), schizophrenia (Schlicker et alNaunyn-Schmiedeberg's Arch. Pharmacol., 1996, 353, 290-294); (also see;Stark et al Drugs Future, 1996, 21, 507 and Leurs et al Progress in DrugResearch, 1995, 45, 107 and references cited therein). Histamine H₃antagonists, alone or in combination with a histamine H₁ antagonist, arereported to be useful for the treatment of upper airway allergicresponse (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). Recently,a histamine H₃ antagonist (GT-2331) was identified and is beingdeveloped by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5, 1998;Bioworld Today, Mar. 2, 1999) for the treatment of CNS disorders.

As noted, the prior art related to histamine H₃ ligands has beencomprehensively reviewed (“The Histamine H ₃ Receptor—A Target for NewDrugs”, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998). Withinthis reference the medicinal chemistry of histamine H₃ agonists andantagonists was reviewed (see Krause et al and Phillips et alrespectively). The importance of an imidazole moiety containing only asingle substitution in the 4 position was noted together with thedeleterious effects of additional substitution on activity. Particularlymethylation of the imidazole ring at any of the remaining unsubstitutedpositions was reported to strongly decrease activity. Additionalpublications support the hypothesis that an imidazole function isessential for high affinity histamine H₃ receptor ligands (See, Ali etal J. Med. Chem., 1999, 42, 903 and Stark et al, Drugs Future, 1996, 21,507 and references cited therein). However many imidazole containingcompounds are substrates for histamine methyl transferase, the majorhistamine metabolizing enzyme in humans, which leads to shortened halflives and lower bioavailability (See, Rouleau et al J. Pharmacol. Exp.Ther. 1997, 281, 1085). In addition, imidazole containing drugs, viatheir interaction with the cytochrome P450 monooxygenase system, canresult in unfavorable biotransformations due to enzyme induction orenzyme inhibition. (Kapetanovic et al Drug Metab. Dispos. 1984, 12, 560;Sheets et al Drug Metab. Dispos. 1984, 12, 603; Back, et al Br. J.Pharmacol. 1985, 85, 121; Lavrijsen et al Biochem. Pharmacol. 1986, 35,1867; Drug Saf., 1998, 18, 83). The poor blood brain barrier penetrationof earlier histamine H₃ receptor ligands may also be associated with theimidazole fragment (Ganellin et al Arch. Pharm. (Weinheim, Ger.) 1998,331, 395).

More recently, several publications have described histamine H₃ ligandsthat do not contain an imidazole moiety. For example; Ganellin et alArch. Pharm. (Weinheim, Ger.) 1998, 331, 395; Walczynski et al Arch.Pharm. (Weinheim, Ger.) 1999, 332, 389; Walczynski et al Farmaco 1999,684; Linney et al J. Med. Chem. 2000, 2362; Tozer and Kalindjian Exp.Opin. Ther. Patents 2000, 10, 1045-1055; U.S. Pat. No. 5,352,707; PCTApplication W099/42458, Aug. 26, 1999; and European Patent Application0978512, Feb. 9, 2000.

The compounds of the present invention do not contain the imidazolemoiety, and its inherent liabilities, and maintain potency at the humanH₃ receptor. Thus in the present invention receptor binding wasdetermined using the human histamine H₃ receptor (See Lovenberg et alMol. Pharmacol. 1999, 1107). Screening using the human receptor isparticularly important for the identification of new therapies for thetreatment of human disease. Conventional binding assays for example aredetermined using rat synaptosomes (Garbarg et al J. Pharmacol. Exp.Ther. 1992, 263, 304), rat cortical membranes (West et al Mol.Pharmacol. 1990, 610), and guinea pig brain (Korte et al Biochem.Biophys. Res. Commun. 1990, 978). Only limited studies have beenperformed previously using human tissue but these allude to significantdifferences in the pharmacology of rodent and primate receptors (West etal Eur. J. Pharmacol. 1999, 233).

We now describe a series of aryloxyalkylamines with the ability tomodulate the activity of the histamine receptor, specifically the H₃receptor, without the inherent problems associated with the presence ofan imidazolyl moiety.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I):

wherein R_(a) and R_(b) are independently C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl,

(C₃₋₈ cycloalkyl) C₁₋₆ alkyl, or taken together with the nitrogen towhich they are attached form a 4-7 membered heterocyclyl optionallyincluding up to 3 additional heteroatoms;

n is 0-4;

one of R₁, R₂, and R₃ is G, and the remaining two are hydrogen or halo;

G is a nitrogen-containing group selected from one of the following:

—OL₁Q, -L₂Q, —N(L₁Q)R₅, -L₃C(L₁Q)R₆R₇, —C(L₁Q)R₆R₇,

wherein:

L₁ is C₂₋₆ alkylene, C₃₋₈ cycloalkylene, C₄₋₆ alkenylene, C₄₋₆alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆alkylene, (C₂₋₅ heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, or(C₂₋₅ heteroaryloxy)C₁₋₆ alkylene;

L₂ is C₁₋₆ alkylene, C₃₋₈ cycloalkylene, C₃₋₆ alkenylene, C₃₋₆alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆alkylene, (C₁₋₅ heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅heteroaryloxy)C₁₋₆ alkylene, or (C₁₋₅ heteroarylthio)C₁₋₆ alkylene;

L₃ is C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, C₂₋₅ alkanoyl,(phenyl)C₁₋₆ alkylene, phenyl, naphthyl, (naphthyl)C₁₋₆ alkylene, C₁₋₅heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅heteroaryloxy)C₁₋₆ alkylene, or C₂₋₅ heteroaryl;

L₄ is C₁₋₅ alkylene;

L₅ is C₁₋₅ alkylene;

L₆ is C₁₋₅ alkylene;

L₇ is C₁₋₅ alkylene or absent;

Q is —NR₈R₉ or a non-aromatic C₂₋₁₅ heterocyclyl ring system containingat least one nitrogen atom and optionally between 1 and 3 additionalheteroatoms selected from O, S, and N in each ring;

each of R₅ and R₆ is independently selected from hydrogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇ cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅heterocyclyl, and (C₂₋₇ heterocyclyl)C₁₋₆ alkylene;

R₇ is H, hydroxyl, halo, C₂₋₆ alkoxy or absent where the carbon linkingL₆ and L₇ (or bonded to R₆) participates in a double bond;

each of R₈ and R₉ is independently selected from hydrogen, C₁₋₈ alkyl,C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇ cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅heterocyclyl, phenyl, (C₂₋₁₅ heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene;

R₁₀ is H, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, (C₂₋₁₅ heterocyclyl)C₁₋₆ alkylene, or (phenyl)C₁₋₆ alkylene;

wherein each of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl,alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each beindependently and optionally substituted with between 1 and 3substituents selected from halo, amino, nitro, hydroxyl, and C₁₋₃ alkyl;

wherein substituents of Q can be further selected from carboxamide, C₂₋₆alkyl, C₁₋₈ heterocyclyl, N(C₁₋₆ alkyl)(C₁₋₈ heterocyclyl), NH(C₁₋₈heterocyclyl), (C₁₋₈ heterocyclyl) C₁₋₃ alkylene, O(C₁₋₈ heterocyclyl),C₁₋₆ alkoxy, (phenyl)C₃₋₆ cycloalkyl-O—, phenyl, (phenyl) C₁₋₃ alkylene,N(C₁₋₆ alkyl)[(phenyl)C₁₋₃ alkylene], and (phenyl)C₁₋₃ alkylene-O— whereeach of above heterocyclyl, phenyl, and alkyl groups may be optionallysubstituted with from 1 to 3 substituents independently selected fromhalogen, nitro, cyano, and C₁₋₃ alkyl;

or a pharmaceutically acceptable salt, ester, or amide thereof.

The invention also features a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier; andmethods of preparing or formulating such compositions. A composition ofthe invention may further include more than one compound of theinvention, or a combination therapy (combination formulation orcombination of differently formulated active agents).

The invention also provides methods of treating certain conditions anddiseases, each of which methods includes administering a therapeuticallyeffective (or jointly effective) amount of a compound or composition ofthe invention to a subject in need of such treatment. The disclosedcompounds are useful in methods for treating or preventing neurologicdisorders including sleep/wake and arousal/vigilance disorders (e.g.insomnia and jet lag), attention deficit hyperactivity disorders (ADHD),learning and memory disorders, cognitive dysfunction, migraine,neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof. For example, the invention featuresmethods for preventing, inhibiting the progression of, or treating upperairway allergic response, asthma, itch, nasal congestion and allergicrhinitis.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of ahistamine H₁ antagonist, such as loratidine (CLARITIN™), desloratidine(CLARINEX™), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for thetreatment of allergic rhinitis, nasal congestion, and allergiccongestion.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method, including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of aneurotransmitter re-uptake blocker, such as a selective serotoninre-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine ornorepinephrine re-uptake inhibitor, including fluoxetine (PROZAC™),sertraline (ZOLOFT™), paroxetine (PAXIL™) and amitryptyline, for thetreatment of depression, mood disorders or schizophrenia.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides non-imidazole aryloxyalkylamines usefulfor the treatment of disorders and conditions modulated by a histaminereceptor.

A. Terms

Certain terms are defined below and by their usage throughout thisdisclosure.

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine, or monovalent radicals thereof.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, shall include straight and branched carbon chains.For example, alkyl radicals include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unlessotherwise noted, “lower” when used with alkyl means a carbon chaincomposition of 1-4 carbon atoms. “Alkylene” refers to a bivalenthydrocarbyl group, such as methylene (CH₂), ethylene (—CH₂—CH₂—) orpropylene (—CH₂CH₂CH₂—).

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “cycloalkyl” shall denote athree- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, “cycloalkenyl” shall denote athree- to eight-membered, partially unsaturated, monocyclic, carbocyclicring structure, wherein the ring structure contains at least one doublebond. Suitable examples include cyclohexenyl, cyclopentenyl,cycloheptenyl, cyclooctenyl, cyclohex-1,3-dienyl and the like.

As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.Divalent radicals include phenylene (—C₆H₄—) which is preferablyphen-1,4-diyl, but may also be phen-1,3-diyl.

As used herein, unless otherwise noted, “aralkyl” shall mean any alkylgroup substituted with an aryl group such as phenyl, naphthyl and thelike. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.

As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any five-, six-, orseven-membered monocyclic, nine or ten membered bicyclic or thirteen orfourteen membered tricyclic ring structure containing at least oneheteroatom moiety selected from the group consisting of N, O, SO, SO₂,(C═O), and S, and preferably N, O, or S, optionally containing one tofour additional heteroatoms in each ring. In some embodiments, theheterocyclyl contains between 1 and 3 or between 1 and 2 additionalheteroatoms. Unless otherwise specified, a heterocyclyl may besaturated, partially unsaturated, aromatic or partially aromatic. Theheterocyclyl group may be attached at any heteroatom or carbon atomwhich results in the creation of a stable structure.

Exemplary monocyclic heterocyclic groups can include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl,4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl, azetidinyl and the like.

For example, where Q is a non-aromatic nitrogen-containing heterocyclyl,preferred values for Q include piperidyl, piperazinyl, pyrrolinyl,pyrrolidinyl, morpholinyl, and N—(C1-6 alkyl) piperazinyl. These may belinked to the rest of the molecule by a nitrogen or a carbon atom; ingeneral, N-linked heterocyclyls are preferred. Q can be substituted withbetween 1 and 3 substituents selected from pyridyl, pyrimidyl, furyl,thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl,2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, and pyrrolyl. Examples ofsubstituted Q, wherein the substituent comprises a heterocyclyl,include: 4-(4-chloropyridin-2-yl)amino-piperidin-1-yl;4-(4-chloropyrimidin-2-yl)amino-piperidin-1-yl;2-([1,2,4]triazol-1-yl)methyl-morpholin-1-yl;3-(pyrazin-2-yl)piperidin-1-yl; 4-(pyrazol-1-yl)piperidin-1-yl;4-(pyrimidin-2-yl)piperazin-1-yl; 4-(furan-2-yl)methylpiperazin-1-yl;4-(thiophen-2-yl)methylpiperazin-1-yl;4-(4-chloropyridin-2-yl)-[1,4]diazepan-1-yl; and5-(isoxazol-5-yl)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl.

Exemplary bicyclic heterocyclic groups include benzthiazolyl,benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl (such as1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (suchas 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl,

and the like.

Exemplary tricyclic heterocylclic groups include acridinyl,phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.

Preferred heterocyclyl groups include morpholinyl, piperidinyl,piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl, acridinyl, azepinyl, hexahydroazepinyl,azetidinyl, indolyl, isoindolyl, thiazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,1,3,4-trihydroisoquinolinyl, 4,5,6,7-tetrahydroindadolyl, benzoxazinyl,benzoaxzolyl, benzthiazolyl, benzimidazolyl, tetrazolyl, oxadiazolyl,

As used herein, unless otherwise noted, the term “heterocyclyl-alkyl” or“heterocyclyl-alkylene” shall denote any alkyl group substituted with aheterocyclyl group, wherein the heterocycly-alkyl group is bound throughthe alkyl portion to the central part of the molecule. Suitable examplesof heterocyclyl-alkyl groups include, but are not limited topiperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl,pyrimidylethyl, and the like.

When a particular group is “substituted” (e.g., alkyl, alkylene,cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes prevention, inhibition of onset, oralleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly in the Schemes andExamples, are as follows:

DBAD = di-tert-butyl azodicarboxylate DCE = 1,2-dichloroethane DCM =dichloromethane DEAD = diethyl azodicarboxylate DMA =N,N-dimethylacetamide DMAP = 4-N,N-dimethylamino- pyridine DME =1,2-dimethoxyethane DMF = dimethylformamide DMSO = dimethylsulfoxide RT= room temperature TEA = triethylamine TFA = trifluoroacetic acid THF =tetrahydrofuran

The next section describes the compounds provided by the invention inmore detail.

B. Compounds

The invention features compounds of formula (I) as described, forexample, in the above Summary section and in the claims. Preferredcompounds include those wherein:

-   (a) NR_(a)R_(b) taken together form piperidyl, methylpiperidyl,    dimethylamino, pyrrolidinyl, diethylamino, methylethylamino,    ethylpropylamino, or dipropylamino;-   (b) NR_(a)R_(b) taken together form piperidyl, pyrrolidinyl, or    diethylamino;-   (c) NR_(a)R_(b) taken together form piperidyl or pyrrolidinyl;-   (d) one of R₂ and R₃ is G;-   (e) R₂ is G;-   (f) R₃ is G;-   (g) n is between 1 and 4, inclusive;-   (h) n is 1;-   (i) L₁ is C₂₋₃ alkylene;-   (j) L₂ is C₁₋₆ alkylene, (C₁₋₅ heteroaryl)C₁₋₆ alkylene, or    -phenyl-C₁₋₆ alkylene;-   (k) L₂ is methylene;-   (l) L₃ is ethylene, vinylene, ethynylene, and phenylene;-   (m) Q is a non-aromatic nitrogen-containing C₂₋₅ heterocyclyl;-   (n) Q is selected from piperidyl, N—(C₁₋₆ alkyl)piperazinyl,    piperazinyl, pyrrolinyl, pyrrolidinyl, and morpholinyl;-   (o) Q is N-morpholinyl or N-piperidinyl, optionally substituted with    between 1 and 3 substituents selected from hydroxyl, carboxamide,    C₁₋₆ alkyl, C₁₋₈ heterocyclyl, N(C₁₋₆ alkyl)(C₁₋₈ heterocyclyl),    NH(C₁₋₈ heterocyclyl), (C₁₋₈ heterocyclyl)C₁₋₃ alkylene, C₁₋₈    heterocyclyl-O—, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl)-O—, phenyl,    (phenyl)C₁₋₃ alkylene, N(C₁₋₆ alkyl)[(phenyl)C₁₋₃ alkylene, and    (phenyl)C₁₋₃ alkylene-O— where each of above heterocyclyl, phenyl,    and alkyl groups may be optionally substituted with from 1 to 3    substituents independently selected from halogen, nitro, cyano, and    C₁₋₃ alkyl;-   (p) Q is substituted with a substituent comprising a C₁₋₆    heterocyclyl group selected from: pyridyl, pyrimidyl, furyl,    thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl,    thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,    (tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,    triazolyl, (pyrrolyl)C₁₋₆ alkylene, and pyrrolyl;-   (q) Q is a substituted or unsubstituted N-morpholinyl;-   (r) Q is NR₈R₉ wherein each of R₈ or R₉ is independently selected    from hydrogen, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇    cycloalkyl)C₁₋₆ alkylene, C₂₋₅ heterocyclyl, phenyl, (C₂₋₅    heterocyclyl)C₁₋₆ alkylene, and (phenyl) C₁₋₆ alkylene;-   (s) one of R₈ and R₉ is hydrogen;-   (t) R₈ is H and R₉ is phenyl or aromatic C₁₋₈ heterocyclyl    optionally substituted with 1-3 substituents selected from halo,    nitro, cyano, and C₁₋₃ alkyl;-   (u) R₉ is phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,    (imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl,    benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene,    tetrazolyl, (triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆    alkylene, and pyrrolyl;-   (v) NR_(a)R_(b) taken together form piperidyl, methylpiperidyl,    dimethylamino, pyrrolidinyl, diethylamino, methylethylamino,    ethylpropylamino, or dipropylamino; (w) NR_(a)R_(b) taken together    form piperidyl, pyrrolidinyl, or diethylamino;-   (x) n is 1;-   (y) G is selected from:    -   (1) formula (i) wherein L₄ and L₅ are independently selected        from C₂₋₃ alkylene,    -   (2) formula (iii) wherein L₆ is C₂₋₃ alkylene and L₇ is C 2-3        alkylene or absent,    -   (3) L₂Q wherein L₂ is C₁₋₆ alkylene, phenyl C₁₋₄ alkylene, or        (aromatic C₁₋₅ heterocyclyl)C₁₋₄ alkylene, and    -   (4) OL₁Q wherein L₁ is C₂₋₃ alkylene;-   (z′) G is selected from:    -   (1) formula (i) wherein L₄ and L₅ are each C₂ alkylene,    -   (2) formula (iii) wherein each of L₆ and L₇ is C₂ alkylene, and    -   (3) L₂Q wherein L₂ is methylene;-   (z) G is L₂Q;-   (aa) R₁₀ is H, branched C₃₋₆ alkyl, or benzyl;-   (bb) R₁₀ is isopropyl or benzyl;-   (cc) Q is a non-aromatic C₂₋₅ heterocyclyl;-   (dd) Q is selected from piperidyl, N—(C₁₋₆ alkyl)piperazinyl,    piperazinyl, pyrrolinyl, pyrrolidinyl, and morpholinyl;-   (ee) Q is a non-aromatic C₂₋₅ heterocyclyl;-   (ff) Q is selected from piperidyl, N—(C₁₋₆ alkyl)piperazinyl,    piperazinyl, pyrrolinyl, pyrrolidinyl, and morpholinyl;-   (gg) Q is selected from piperidyl, N—(C₁₋₆ alkyl)piperazinyl,    piperazinyl, pyrrolinyl, pyrrolidinyl, and morpholinyl;-   (hh) NR_(a)R_(b) taken together form piperidyl, pyrrolidinyl, or    diethylamino;-   (ii) n is 1;-   (jj) R₇ is hydroxyl, halo, or absent where one of L₆ and L₇ provides    a double bond to the carbon atom to which R₆ and R₇ are attached; or-   (kk) Combinations of the above.

Examples of preferred compounds include:Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-amine,Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine,[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenoxy]-ethyl}-amine,Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine, andDibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-amine.

Additional preferred compounds include:Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine, and(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine.

Additional examples of preferred compounds include:4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine,1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidine,1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy}-propyl)-piperidine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine, 2-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-amine,1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic acidamide,Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-amine, Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine,2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine,2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol,1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine,1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine,1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane,1-[3-(2′-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one,1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propyl)-piperidine.

The invention also features compounds such as:1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperidine,Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzoimidazole,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole,1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane,1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole,Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine,2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-ethanol,4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline,[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine,Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-amine,Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine,Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,5-(3-Piperidin-1-yl-propoxy)-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrimidine,(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,1-Methyl-4-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperazine,1-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline, and(4-Chloro-phenyl)-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine.

Additional examples include:4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine,1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidine,1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy}-propyl)-piperidine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine,2-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-amine,1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic acidamide,Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-amine,Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine,2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine,Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine,2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol,1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine,1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,andEthyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine.

More preferred compounds of the invention include:1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane,1-[3-(2′-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one,1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propyl)-piperidine,1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine,4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperidine,Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzoimidazole,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl,1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole,1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane,1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine,5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole,Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine,2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-ethanol,4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine,2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline,Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine,1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline,[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine,1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine,Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-amine,Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine,Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine, and[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine.

The invention also features compounds such as:1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine,1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride,1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine,1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride, and1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine. Morepreferred compounds include:1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine,1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine,1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine, and1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine.

Further examples include: (A)1-{3-[2′-(1-Isopropyl-piperidin-4-yl)-biphenyl-4-yloxy]-propyl}-piperidine,1-(3-{4-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-phenoxy}-propyl)-piperidine,and1-{3-[4-(1-Isopropyl-piperidin-4-ylmethyl)-phenoxy]-propyl}-piperidine;(B) 1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine,1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol, and1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol; (C)1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine, and1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol; (D){3-Furan-2-yl-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-propyl}-dimethyl-amine,4-{3-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-3-pyrimidin-2-yl-propyl}-morpholine,4-{4,4,4-Trifluoro-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-butyl}-morpholine,and4-{4,4,4-Trifluoro-3-[4-(3-piperidin-1-yl-propoxy)-phenyl]-butyl}-morpholine;and (E)(2-Morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyridin-2-yl-amine,Isopropyl-(2-morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-phenyl]-amine,and(2-Morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-phenyl]-thiazol-2-ylmethyl-amine.

The invention also provides compounds that are useful as syntheticintermediates of the compounds of the invention. Such compounds, whichthemselves may or may not have pharmaceutical activity, include thoseprovided in the schemes and synthetic examples.

The invention also contemplates compounds isotopically-labelled to bedetectable by positron emission tomography (PET) or single-photonemission computed tomography (SPECT) useful for studying H₃-mediateddisorders.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-tri methylbenzoate(mesitoate)

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of Amides Include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special —NH Protective Groups

Examples of special NH protective groups include:

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN-(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

Monoprotection of Dicarbonyl Compounds

Selective Protection Of α- and β-Diketones

Examples of selective protection of α- and β-diketones include enamines,enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl,morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, andtrimethylsilyl.

Cyclic Ketals, Monothio and Dithio Ketals

Examples of cyclic ketals, monothio and dithio ketals includebismethylenedioxy derivatives and tetramethylbismethylenedioxyderivatives.

Protection for the Carboxyl Group

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,

2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl,

2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N-phenyl and N,N′-diisopropyl.

The compounds of the invention can be prepared according to the methodsdescribed in the next section.

C. Synthesis

The compounds of the invention can be prepared according to traditionalsynthetic organic methods and matrix or combinatorial chemistry methods,as shown in Schemes 1-10 below and in Examples 1-97. A person ofordinary skill will be aware of variations and adaptations of theschemes and examples provided to achieve the compounds of the invention.

One skilled in the art will recognize that synthesis of the compounds ofthe present invention may be effected by purchasing intermediate orprotected intermediate compounds described in any of the Schemesdisclosed herein. Throughout the schemes when the reacting functionalityis located at R₃, one skilled in the art will recognize that the choiceof R₃ is illustrative only and that the reacting functionality couldalso be located at R₁ and R₂ also.

One skilled in the art will further recognize that during any of theprocesses for preparation of the compounds of the present invention, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups, such as those described in“Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, 1991. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Generally, a compound of formula (II), a known compound or compoundprepared by known methods is reacted in Step A to form the compound offormula (IV) and then reacted in Step B to form the compound of formula(I). Alternatively, the compound of formula (II) is reacted with acompound of formula (VI) in Step C to form the compound of formula (I).Specifically, a compound of formula (II), wherein R₁, R₂, R₃ are asdefined is reacted with a compound of formula (III) where X₁ and X₂ areeach independently selected from the group consisting Cl, Br, I,tosylate, mesylate, and the like wherein X₁ is selected such that underthe reaction conditions, X₁ is preferentially displaced (rather than X₂;i.e. such that the compound of formula (III) is selectively coupled interms of which end of the molecule is bonded to the compound of formula(II)), in the presence of a base such as sodium hydroxide, TEA, sodiumhydride, potassium carbonate, and the like, in an organic solvent suchas DCM, THF, DMF, DMA, and the like, to yield the corresponding compoundof formula (IV). The compound of formula (IV) is reacted with a compoundof formula (V), in the presence of a base such as sodium hydroxide, TEA,potassium carbonate, and the like, in an organic solvent such as DCM,THF, DMF, and the like, to yield the corresponding compound of formula(I).

In an alternative embodiment a compound of formula (II) may be reactedwith a compound of formula (VI) where X₁ is as defined, in the presenceof a base such as sodium hydroxide, TEA, sodium hydride, potassiumcarbonate, and the like, in an organic solvent such as DCM, THF, DMF,DMA, and the like, to yield the corresponding compound of formula (I).

In a further alternative embodiment a compound of formula (II) isreacted with a compound formula (III), or a compound of formula (VI) inwhich X₁ is OH, under Mitsunobu conditions, (in the presence oftriphenylphosphine or polymer supported triphenyl phosphine and DBAD orDEAD, in an organic solvent such as DCM, THF, and the like), to yieldthe corresponding compounds of formula (IV) or (I).

A compound of formula (VIII) may be prepared according to the processoutlined in Scheme 2. More particularly, a compound of formula (I),wherein R₃ is —COR₅ is reacted with an amine of formula (VII), in thepresence of a reducing agent such as sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, hydrogen gas in thepresence of a catalyst, and the like, in a solvent such as methanol,ethanol, 1,2-dichloroethane, trifluoroethanol, and the like, to yieldthe compound of formula (VIII). One skilled in the art will recognizethat addition of acid to decrease the pH of the reaction mixture to a pHof less than about 7 may be necessary to effect the reaction, whereinthe acid is added as needed. Examples of appropriate acids includeacetic acid, hydrochloric acid, and the like. When R₂₀ is H, thecompound of formula (VII) is preferably reacted with a reducing agentsuch as sodium cyanoborohydride or sodium triacetoxyborohydride.

In an alternative embodiment, a compound of formula (VIII) may beprepared according to the processes outlined in Scheme 3.

A compound of formula (II) wherein R₃ is —COR₂₀ is reacted with acompound of formula (VII) according to the procedures of Scheme 2 toafford a compound of formula (IX) which is further reacted according tothe procedures of Scheme 1, either Steps A and B or Step C, to afford acompound of formula (VIII).

Scheme 4 provides guidance for the preparation of compounds of formula(XV) and (XVI) where Z can be substituted or unsubstituted phenyl orheterocycle and W is absent or —COR₂₀, or —OY, where Y is a protectinggroup. Preferred compounds are those in which Z is substituted phenyl,thienyl, pyridinyl, pyrimidinyl or pyrrolyl.

A compound of formula (II) or (I) is reacted with a compound of formula(XI) in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium (0), and the like, in the presence of a base such as sodiumcarbonate, potassium carbonate, and the like, in an organic solvent suchas toluene, benzene, xylene, and the like, to yield the correspondingcompounds of formula (XII) and (XIII) respectively. A compound offormula (XIII) wherein W is —COR₂₀ is reacted with a compound of formula(VII) according to the procedures of Scheme 2 to afford a compound offormula (XVI). Alternatively a compound of formula (XV) may be preparedfrom a compound of formula (XIII) wherein W is —OY. The protecting groupY is first removed under the appropriate conditions to afford thecorresponding hydroxyl compound which is reacted with a compound offormula (XIV), wherein X₁ is as defined, under the conditions describedfor Step A, Scheme 1, to afford a compound of formula (XV).

Compounds of formula (XXI) may be prepared according to the processesoutlined in Scheme 5. A compound of formula (XII) where Y is aprotecting group and R₃ is a halogen, preferably Br or I, morepreferably I, is reacted with an organolithium reagent such asn-butyllithium in an organic solvent such as THF, diethyl ether and thelike, and then reacted with a compound of formula (XVII) to afford acompound of formula (XVIII). The compound of formula (XVIII) is thenreacted with a reducing agent such as sodium borohydride or sodiumcyanoborohydride, and the like, in the presence of an acid such as TFA,HCl or acetic acid in an organic solvent such as THF or diethyl ether toyield the corresponding compound of formula (XIX). Alternatively thecompound of formula (XVIII) may be reacted with hydrogen in the presenceof a catalyst such as palladium on carbon or triethylsilane in thepresence of TFA to yield a compound of formula (XIX). A compound offormula (XX) may be obtained upon removal of the protecting group Y fromthe compound of formula (XIX) followed by reaction under the conditionsdescribed in Scheme 1. A compound of formula (XXI) may be obtained froma compound of formula (XX) via removal of the group Y₂. One skilled inthe art will recognize that in this Scheme both Y and Y₂ may beprotecting groups. One skilled in the art will further recognize andunderstand the concept of orthogonal protection such that the groups Yand Y₂ may be removed separately and at the appropriate points in thesynthetic procedure. The compound of formula (XXI) may also be reactedfurther via the procedures of Scheme 2 (reductive amination) or viaN-alkylation with a compound of formula (XIVa) to afford a compound offormula (XXII).

Compounds of formula (XXVII) may be prepared according to the processesoutlined in Scheme 6. Thus a compound of formula (XII) where R₃ isselected from Br and I, and is preferably I, is reacted with a compoundof formula (XXIII) in the presence of a catalyst such astris(dibenzylidineacetone)dipalladium(0), and the like, in the presenceof a base such as sodium t-butoxide, cesium carbonate, triethylamine,potassium carbonate, and the like, in an organic solvent such as THF ordioxane, and the like, preferably in the presence of BINAP(2,2′-bis(diphenylphosphino)-1,1′-dinaphthyl) and 18-Crown-6 (a crownether), to yield the corresponding compound of formula (XXIV).

A compound of formula (XXV) may be obtained upon removal of theprotecting group Y from the compound of formula (XXIV) followed byreaction under the conditions described in Scheme 1. A compound offormula (XXVI) may be obtained from a compound of formula (XXV) viaremoval of the group Y₂. The compound of formula (XXVI) may also bereacted further via the procedures of Scheme 2 (reductive amination) orvia N-alkylation with a compound of formula (XIVa) to afford a compoundof formula (XXVII).

In an alternative embodiment a compound of formula (XXVI) may beobtained from a compound of formula (XXVIII) according to the processesoutlined in Scheme 7. A compound of formula (XXVIII) where R₁₀ is H isreacted with an alkyl chloroformate or dialkyldicarbonate and the likeif necessary in the presence of an amine base to yield the correspondingcompound of formula (XXIX) where Y represents a carbamate protectinggroup. In a preferred embodiment the chloroformate isethylchloroformate, benzylchloroformate,2,2,2-trichloroethylchloroformate, alpha-chloroethylchloroformate andthe dialkyldicarbonate is di-tert-butyldicarbonate. A particularlypreferred embodiment uses di-tert-butyldicarbonate. The compound offormula (XXIX) is reacted according to the procedures of Scheme 1 toafford compound (XXX) whereupon removal of the carbamate protectinggroup affords compound of formula (XXVI). In a preferred embodiment atert-butyl carbamate is removed under acidic conditions using TFA or HClin a solvent, for example TFA in DCM or HCl in ether.

Compounds of formula (XXXV) may be prepared according to the proceduresoutlined in Scheme 8. Compounds of formula (XXXI) are reacted accordingto the processes outlined in Scheme 1 to give compounds of formula(XXXII). Removal of the protecting group Y affords compound of formula(XXXIII). In a preferred embodiment the group Y is a benzyl group, thusthe compound of formula (XXXII) is reacted with with hydrogen gas orammonium formate, in the presence of a catalyst such as palladium oncarbon, and the like, in a solvent such as methanol, ethanol, and thelike, (i.e. catalytic hydrogenolysis) to yield the correspondingcompound of formula (XXXIII). The compound of formula (XXXIII) isreacted with a compound of formula (XXXIV) to afford a compound offormula (XXXV). Thus the compound of formula (XXXIII) is reacted with acompound of formula (XXXIV) under Mitsunobu conditions, (in the presenceof triphenylphosphine or polymer supported triphenyl phosphine and DBADor DEAD, in an organic solvent such as DCM, THF, and the like), to yieldthe corresponding compound of formula (XXXV).

In a particular embodiment of Scheme 8, illustrated in Scheme 9, thecompound of formula (XXXVI) may be prepared via a double Mitsunobureaction between a compound of formula (XXXVII) and a compound offormula (XXXIV). Thus the compound of formula (XXXVII) is reacted with acompound of formula (XXXIV) under Mitsunobu conditions, (in the presenceof triphenylphosphine or polymer supported triphenyl phosphine and DBADor DEAD, in an organic solvent such as DCM, THF, and the like), to yieldthe corresponding compound of formula (XXXVI).

Compounds of formula (XXXVIII) are prepared as outlined in Scheme 10, byreacting compounds of formula (XL), prepared as outlined in Scheme 4,with a compound of formula (XLI) to afford a compound of formula (XLII).The compound of formula (XLII) may be reacted further to give a compoundof formula (XXXVIII). In a particular embodiment compound of formula(XXXIX) contains the protecting group Y which is removed to afford acompound of formula (XL). The compound of formula (XL) is reacted with acompound of formula (XLI) in the presence of a base to yield a compoundof formula (XLII). In a preferred embodiment the compound of formula(XLI) contains NY where NY is2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane. The protecting group Yof the compound of formula (XXXXII) is removed and the primary amineproduct reacted via alkylation or reductive amination to afford compoundof formula (XXXVIII). In an alternative embodiment a compound of formula(XXXVIII) may be prepared from a compound of formula (XL) according tothe procedures outlined in Scheme 1.

D. Formulation, Administration, and Therapy

The disclosed compounds, alone or in combination (with, for example, ahistamine H₁ receptor antagonist), are useful for treating or preventingneurologic disorders including sleep/wake and arousal/vigilancedisorders (e.g. insomnia and jet lag), attention deficit hyperactivitydisorders (ADHD), learning and memory disorders, cognitive dysfunction,migraine, neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof.

1. Formulation and Administration

The compounds or compositions of the invention may be formulated andadministered to a subject by any conventional route of administration,including, but not limited to, intravenous, oral, subcutaneous,intramuscular, intradermal and parenteral administration. The quantityof the compound which is effective for treating each condition may vary,and can be determined by one of ordinary skill in the art.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali ml salts, e.g., sodium or potassiumsalts; alkaline earth ml salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts.

Thus, representative pharmaceutically acceptable salts include thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preption of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. In additionto salts, the invention provides the esters, amides, and other protectedor derivatized forms of the described compounds.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists or SSRIs. Preferably thesecompositions are in unit dosage forms such as pills, tablets, caplets,capsules (each including immediate release, timed release and sustainedrelease formulations), powders, granules, sterile parenteral solutionsor suspensions (including syrups and emulsions), metered aerosol orliquid sprays, drops, ampoules, autoinjector devices or suppositories;for oral parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 5 to about 1000 mg ofthe active ingredient of the present invention. Examples include 5 mg, 7mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg,and so on. The tablets or pills of the disclosed compositions can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can besepted by an enteric layer which serves to resist disintegration in thestomach and permits the inner component to pass intact into the duodenumor to be delayed in release. A variety of material can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of ADHD is required.

The daily dosage of the products may be varied over a wide range from 1to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thesubject to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.02 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.05mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

2. Combination Therapy

The disclosed compounds are useful in combination with other therapeuticagents, including H₁ receptor antagonists, H₂ receptor antagonists, andneurotransmitter modulators such as SSRIs and non-selective serotoninre-uptake inhibitors (NSSRIs).

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated, at least in part, by themodulation of one or more histamine receptors. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. Combinations of three or moredrugs are analogously possible. Methods of combination therapy includeco-administration of a single formulation containing all active agents;essentially contemporaneous administration of more than one formulation;and administration of two or more active agents separately formulated.

E. Examples Example 1

3-Piperidin-1-yl-propan-1-ol

A solution of potassium carbonate (24.9 g) and piperidine (130 mL) in1:1 ethanol-water (130 mL) was treated with 3-bromopropan-1-ol (25.0 g).The resulting mixture was stirred vigorously for 20 h. Dichloromethane(200 mL) and water (50 mL) were added and the aqueous phase wasextracted with dichloromethane (2×100 mL). The combined organic extractswere dried (magnesium sulfate) and evaporated in vacuo. Kugelrohrdistillation of the residue (5-10 mm Hg, 120° C.) gave the titlecompound as a colorless oil (13.9 g).

Example 2

1-(3-Chloro-propoxy)-4-iodo-benzene

A suspension of 4-iodophenol (20 g), 1-bromo-3-chloropropane (18 mL),and potassium carbonate (38 g) in acetone (250 mL) was heated at refluxfor 16 h and allowed to cool to room temperature. The suspension wasfiltered, and the filtrate was evaporated in vacuo. Kugelrohrdistillation of the residue (5-10 mm Hg, 210° C.) gave the titlecompound as a white crystalline solid (22 g).

Example 3

4-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of 1-(4-hydroxyphenyl)piperazine (12.0 g) intetrahydrofuran (50 mL) was added dropwise a solution of di-tert butyldicarbonate (72 ml of a 1M solution). Saturated aqueous sodiumbicarbonate (60 ml) was added and the resulting mixture was stirred atroom temperature for 16 h. The reaction was extracted with ethyl acetate(700 ml). The organic phase was washed with water (50 ml), brine (5 ml),and dried (magnesium sulfate). Solvent was removed in vacuo and theresidue was triturated with hexanes, giving the title compound as abrown solid (16.3 g).

Example 4

4-[4-(3-Chloro-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butylester

A suspension of tert-butyl 1-(4-(4-hydroxy)phenyl)piperazine carboxylate(5.0 g), 1-bromo-3-chloropropane (3.6 mL), and potassium carbonate (7.4g) in acetone (60 mL) was heated at reflux for 24 h and allowed to coolto room temperature. The suspension was filtered, and the filtrate wasevaporated in vacuo. Silica gel chromatography of the residue (30% ethylacetate/hexane) gave the title compound as a light yellow solid (5.3 g).

Example 5

1-[3-(4-Iodo-phenoxy)-propyl]-piperidine

A suspension of 4-(3-chloro-1-propoxy)iodobenzene (5 g), piperidine (2.2mL), sodium carbonate (2.7 g), and potassium iodide (140 mg) inn-butanol (30 mL) was heated in a 105° C. bath for 18 h. The resultingmixture was allowed to cool to room temperature, diluted with water (50mL), and extracted with methylene chloride (2×20 mL). The combinedorganic phases were dried (magnesium sulfate), and evaporated in vacuo.Kugelrohr distillation of the residue (5 mm Hg, 260° C.) gave the titlecompound as a white crystalline solid (4.8 g).

Example 6

1-[3-(4-Benzyloxy-phenoxy)-propyl]-piperidine

A suspension of 4-benzyloxyphenol (30 g), 1-bromo-3-chloropropane (30mL) and potassium carbonate (62 g) in acetone (400 mL) was heated atreflux for 25 h and allowed to cool to room temperature. The suspensionwas filtered, and the filtrate was evaporated in vacuo.Recrystallization of the residue (hexanes) gave fine needles (29 g). Asuspension of this material (32 g), piperidine (14.8 mL), sodiumcarbonate (18.3 g), and potassium iodide (95 mg) in n-butanol (140 mL)was heated in a 105° C. bath for 28 h. The resulting mixture was allowedto cool to room temperature, diluted with water (100 mL), and extractedwith methylene chloride (3×100 mL). The combined organic phases weredried (magnesium sulfate), and evaporated in vacuo. Recrystallization ofthe residue (ethanol) gave the title compound as a white crystallinesolid (29 g).

Example 7

4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester

A suspension of the product of Example 4 (1.0 g), pyrrolidine (435 mg),sodium carbonate (297 mg), and potassium iodide (9.3 mg) in n-butanol (5mL) was heated in a 100° C. bath for 16 h. The resulting mixture wasallowed to cool to room temperature, and filtered through celite. Thefiltrate evaporated in vacuo. Silica gel chromatography of the residue(5% 2M ammonia-methanol/dichloromethane) gave the title compound as ayellow solid (900 mg).

Example 8

4-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester

A suspension of the product of Example 4 (3.0 g), piperidine (1.4 g),sodium carbonate (900 mg), and potassium iodide (28 mg) in n-butanol (15mL) was heated in a 100° C. bath for 16 h. The resulting mixture wasallowed to cool to room temperature, and filtered through celite. Thefiltrate evaporated in vacuo. Silica gel chromatography of the residue(5% 2M methanolic ammonia/dichloromethane) gave the title compound as abrown solid (2.3 g).

Example 9

4-(3-Piperidin-1-yl-propoxy)-benzaldehyde

A solution the product of Example 11 (10 g), piperidine (6.5 mL), sodiumcarbonate (8.1 g), and potassium iodide (422 mg) in 1-butanol (60 mL)was heated to 105° C. for 18 h, cooled to RT, diluted with water (50 mL)and extracted with DCM (3×50 mL). The combined organic phases were dried(magnesium sulfate) and evaporated, giving the title compound as ayellow oil (11.5 g).

Example 10

3-(3-Chloro-propoxy)-benzaldehyde

A suspension of 3-hydroxybenzaldenyde (25.0 g), 1-bromo-3-chloropropane(30.4 mL) and potassium carbonate (50.9 g) in acetone (300 mL) washeated under reflux. After 16 h, the resulting mixture was cooled to RTand filtered through a pad of celite. The pad was washed with acetone(3×20 mL). The combined filtrates were concentrated. Chromatography ofthe residue (15-25% ethyl acetate/hexane) gave the title compounds as ayellow oil (14.2 g).

Example 11

4-(3-Chloro-propoxy)-benzaldehyde

A suspension of 4-hydroxybenzaldehyde (40 g), 1-bromo-3-chloropropane(63 mL), and potassium carbonate (136 g) in acetone (920 mL) was heatedto reflux for 16 h. The resulting mixture was filtered, and the filtratewas evaporated. Distillation of the residue (0.5 mm Hg, 220° C.) gavethe title compound as a pale yellow oil that crystallized on standing(46 g).

Example 12

1-[4-(3-Chloro-propoxy)-benzyl]-piperidine

A solution of the product of Example 11 (5.0 g), piperidine (3.1 mL),and acetic acid (2.0 mL) in DCE (100 mL) was treated with sodiumtriacetoxyborohydride (9.3 g). After 16 h, the resulting mixture wasdiluted with water (100 mL) and extracted with DCM (3×50 mL). Thecombined organic phases were dried (magnesium sulfate) and evaporated,giving the title compound as an amber oil (5.3 g).

Example 13

3-(3-Piperidin-1-yl-propoxy)-benzaldehyde

A suspension of the product of Example 10 (4.16 g), potassium carbonate(5.52 g) and piperidine (5.0 mL) in DMF (25.0 mL) was heated to 80° C.for 12 h. The resulting mixture was poured into water (400 mL) andextracted with ethyl acetate (3×50 mL) and the combined extracts weredried over sodium sulfate. Chromatography of the residue (1 to 10% 2Mmethanolic ammonia/DCM) gave the title compound as a yellow oil (3.14g).

Example 14

2-(3-Piperidin-1-yl-propoxy)-benzaldehyde

A suspension of 2-hydroxybenzaldenyde (5.43 g), 1-bromo-3-chloropropane(6.5 mL) and potassium carbonate (13.11 g) in acetone (100 mL) washeated under reflux. After 16 h, the resulting mixture was cooled to RTand poured into water (400 mL) and extracted with ether (3×100 mL). Theorganics were washed with water (3×50 mL) and 1M NaOH (2×50 mL) andbrine. The combined filtrates were concentrated. The excess1-bromo-3-chloropropane was removed by distillation (80° C., 2 mm Hg) togive 1-(3-chloro-propoxy)-benzaldehyde as a yellow oil (8.80 g). Asuspension of this material (4.81 g), potassium carbonate (5.04 g) andpiperidine (5.0 mL) in DMF (5.0 mL) was then heated to 80° C. for 12 h.The resulting mixture was poured into water (400 mL) and extracted withDCM (3×50 mL) and the combined extracts were dried over sodium sulfate.Chromatography of the residue (1-10% 2M methanolic ammonia/DCM) gave thetitle compound as a yellow oil (1.53 g).

Example 15

4-(3-Piperidin-1-yl-propoxy)-phenol

A suspension of the product of Example 6 (2.5 g), ammonium formate (2.7g), and 10% palladium on carbon (2.5 g) in methanol (100 mL) was heatedin a 68° C. bath for 3 h, and allowed to cool to room temperature. Themixture was filtered through Celite, and the filtrate was evaporated invacuo. Saturated aqueous sodium bicarbonate was added, and the mixturewas extracted with dichloromethane (4×30 mL). The combined organicphases were dried (magnesium sulfate) and evaporated in vacuo, yieldingthe title compound as a pink microcrystalline solid (1.3 g) which wasused without further purification. A small sample (100 mg) wasrecrystallized (ethanol) to obtain the title compound as beige prisms(68 mg).

Example 16

4′-(3-Piperidin-1-yl-propoxy)-biphenyl-2-carbaldehyde

A solution of the product of Example 5 (593 mg),tetrakis(triphenylphosphine)palladium(0) (116 mg), and2-formylphenylboronic acid (270 mg) in tetrahydrofuran (11 mL) wastreated with a solution of sodium carbonate (191 mg) in water (2.7 mL).The resulting mixture was heated in a 65° C. bath for 14 h, and allowedto cool to room temperature. Ether (20 mL) and water (10 mL) were added,and the aqueous phase was extracted with ether (2×20 mL). The combinedorganic phases were dried (magnesium sulfate) and evaporated in vacuo.Silica gel chromatography of the residue (2.5% 2Mammonia-methanol/dichloromethane) gave the title compound as a paleyellow oil (175 mg).

Example 17

4-Piperidin-1-ylmethyl-phenol

A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9 mL), andacetic acid (4.7 mL) in DCE (200 mL) was treated with sodiumtriacetoxyborohydride (24 g). After 16 h, the resulting mixture wastreated with saturated aqueous sodium bicarbonate (100 mL) and extractedwith DCM (5×100 mL). The combined organic phases were dried (magnesiumsulfate) and evaporated. Trituration of the residue with ethyl acetategave the title compound as a white crystalline solid (5.5 g).

Example 18

1-{3-[4-(1H-Pyrrol-2-yl)-phenoxy]-propyl}-piperidine

To a stirred solution of the product of Example 5 (4 g) intetrahydrofuran (30 mL) was added tetrakis(triphenylphosphine)palladium(0.76 g). The mixture was stirred at RT for 30 min and then treated witha solution of 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (2.57 g) andsodium carbonate (1.29 g) in water (20 mL). The mixture was heated toreflux for 1.5 d. The tetrahydrofuran was removed under reduced pressureand the aqueous layer was extracted several times with methylenechloride. The combined organic layers were dried (sodium sulfate),filtered and concentrated under reduced pressure to give a black oil(5.42 g). Chromatography (50% ethyl acetate/hexane containing 2%triethylamine) afforded an orange-red oil (3.63 g). This material (3.63g) was dissolved in a mixture of methanol (75 mL) and tetrahydrofuran(40 mL) and treated with sodium methoxide (3.12 g). The mixture wasstirred at RT for 12 h and then additional sodium methoxide was added(1.7 g). After stirring at RT for 12 additional hours, the mixture wasconcentrated under reduced pressure, and the residue partitioned betweendiethyl ether and water. The organic layer was separated and the aqueouslayer extracted several times with diethyl ether. The combined organiclayers were dried (sodium sulfate), filtered and concentrated, yieldingthe title compound (2.68 g).

Example 19

1-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline

A solution of 4-(2-piperidylethoxy)-benzaldehyde (200 mg),1,2,3,4-tetrahydroquinoline (126 mg), and acetic acid (0.11 mL) indichloroethane (2 mL) was treated with sodium triacetoxyborohydride (254mg). After 15 h, the reaction was quenched with saturated aqueous sodiumbicarbonate, and the aqueous phase was extracted with dichloromethane(2x2 mL). The combined organic phases were dried (magnesium sulfate) andevaporated in vacuo. Silica gel chromatography of the residue (2% 2Mammonia-methanol/dichloromethane) gave the title compound as a colorlessviscous oil (51 mg). ¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.8 Hz, 2H),6.97 (d, J=7.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.60-6.52 (m, 2H), 4.41(s, 2H), 4.09 (t, J=6.2 Hz, 2H), 3.36-3.32 (m, 2H), 2.83-2.75 (m, 4H),2.54-2.47 (m, 4H), 2.03-1.97 (m, 2H), 1.64-1.57 (m, 4H), 1.49-1.42 (m,2H).

Example 20

1-[2-(4-Piperidin-1-ylmethyl-phenoxy)-ethyl]-piperidine

A solution of 4-(2-piperidylethoxy)-benzaldehyde (200 mg), piperidine(80 mg), and acetic acid (1 mL of a solution prepared from acetic acid(0.5 mL) in dichloroethane (10 mL)) in dichloroethane (1 mL) was treatedwith sodium triacetoxyborohydride (254 mg). After 17 h, the reaction wasquenched with saturated aqueous sodium bicarbonate, and the aqueousphase was extracted with dichloromethane (2×1 mL). The combined organicphases were dried (magnesium sulfate) and evaporated in vacuo. Silicagel chromatography of the residue (5% 2M ammonia-methanol/ethyl acetate)gave the title compound as a pale yellow oil (69 mg). ¹H NMR (400 MHz,CDCl₃): 7.20 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.08 (t, J=6.1Hz, 2H), 3.39 (s, 2H), 2.75 (t, J=6.1 Hz, 2H), 2.54-2.45 (m, 4H),2.38-2.30 (m, 4H), 1.63-1.52 (m, 8H), 1.47-1.37 (m, 4H).

Example 21

2-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline

1,2,3,4-Tetrahydroisoquinoline (126 mg) was treated with a solution ofacetic acid (1 mL of a solution of acetic acid (1 mL) in dichloroethane(10 mL)) and the resulting solution was added to4-(2-piperidylethoxy)-benzaldehyde (200 mg). The resulting mixture wastreated with sodium triacetoxyborohydride (254 mg). After 15 h, thereaction was quenched with saturated aqueous sodium bicarbonate, and theaqueous phase was extracted with dichloromethane (2×2 mL). The combinedorganic phases were dried (magnesium sulfate) and evaporated in vacuo.Silica gel chromatography of the residue (2% 2Mammonia-methanol/dichloromethane) gave the title compound as a colorlessviscous oil (218 mg). ¹H NMR (400 MHz, CDCl₃): 7.31 (d, J=8.4 Hz, 2H),7.13-7.06 (m, 3H), 7.01-6.96 (m, 1H), 6.91-6.86 (m, 2H), 4.12 (t, J=6.1Hz, 2H), 3.62 (s, 4H), 2.90 (t, J=5.7 Hz, 2H), 2.81-2.71 (m, 4H),2.56-2.47 (m, 4H), 1.66-1.57 (m, 4H), 1.50-1.42 (m, 2H).

Example 22

1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol

A solution of the product of Example 5 (297 mg) in tetrahydrofuran (2mL) was cooled in a dry-ice/acetone bath and treated with n-butyllithium(0.44 mL of a 2.5 M solution in hexane). After 30 min, the resultingsolution was treated with a solution of 1-benzyl-4-piperidone (0.19 mL)in tetrahydrofuran (1 mL). After 15 min, the reaction was allowed towarm to room temperature, and quenched with water (3 mL). Volatiles wereremoved in vacuo, and the residue was extracted with ether (3×5 mL). Thecombined organic phases were dried (magnesium sulfate) and evaporated invacuo. Silica gel chromatography of the residue (3% 2Mammonia-methanol/dichloromethane) gave the title compound as a whitemicrocrystalline solid (80 mg). ¹H NMR (400 MHz, CDCl₃): 7.42-7.22 (m,7H), 6.86 (d, J=8.8 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 3.57 (s, 2H),2.79-2.72 (m, 2H), 2.50-2.33 (m, 7H), 2.16-2.06 (m, 2H), 1.99-1.91 (m,2H), 1.77-1.65 (m, 3H), 1.61-1.54 (m, 4H), 1.47-1.39 (m, 2H)

Example 23

1-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride

A solution of the product of Example 7 (300 mg) in dioxane (5 mL) wastreated with a solution of 4N hydrogen chloride in dioxane (2 mL) for 48h. Volatiles were removed in vacuo, and the residue was triturated withether, giving the title compound as an ivory solid (230 mg). ¹H NMR (400MHz, MeOH-d₄): 7.35-7.33 (d, J=8.9 Hz, 2H), 7.05-7.03 (d, J=8.9 Hz, 2H),4.13 (t, J=5.5 Hz, 2H), 3.73-3.69 (m, 2H), 3.60(bs, 8H), 3.45-3.41 (m,2H), 3.16-3.11 ( m, 2H), 2.27-2.15 (m, 4H), 2.10-2.05 (m, 2H)

Example 24

1-Benzyl-4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-piperazine

A solution of the product of Example 23 (148 mg), benzaldehyde (520 mg),and acetic acid (25 mg) in dichloroethane (3 mL) was treated with sodiumtriacetoxyborohydride (121 mg). After 14 h, the reaction was quenchedwith saturated aqueous sodium bicarbonate, and the aqueous phase wasextracted with dichloromethane (120 mL). The organic phase was dried(magnesium sulfate) and evaporated in vacuo. Silica gel chromatographyof the residue (5% 2M ammonia-methanol/dichloromethane) gave the titlecompound as a light yellow solid (8 mg). ¹H NMR (400 MHz, CDCl₃):7.36-7.24 (m, 5H), 6.94-6.81 (m, 4H), 3.96 (t, J=6.4 Hz, 2H), 3.56 (s,2H), 3.08 (t, J=4.9 Hz, 4H), 2.64-2.60 ( m, 4H), 2.04-1.94 (m, 2H),1.80-1.75 (m, 4H).

Example 25

1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-piperazine hydrochloride

A solution of the product of Example 8 (520 mg) in dioxane (6 mL) wastreated with a solution of 4N hydrogen chloride in dioxane (4 mL) for 48h. Volatiles were removed in vacuo, and the residue was triturated withether, giving the title compound as an ivory solid (750 mg). ¹H NMR (400MHz, MeOH-d₄): 7.16-7.14 (d, J=9.0 Hz, 5H), 6.84-6.96 (d, J=8.9 Hz, 4H),4.10 (t, J=5.6 Hz, 2H), 3.62 (d, J=12.0 Hz, 2H), 3.00 (t, J=12.1 Hz,2H), 2.67-2.21 ( m, 2H), 2.01-1.98 (m, 2H), 1.90-1.76 (m, 3H), 1.70-1.52(m, 1H).

Example 26

1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine

A solution of the product of Example 25 (122 mg), acetone (23 mg), andacetic acid (19 mg) in dichloroethane (3 mL) was treated with sodiumtriacetoxyborohydride (96 mg). After 14 h, the reaction was quenchedwith saturated aqueous sodium bicarbonate, and the aqueous phase wasextracted with dichloromethane (120 mL). The organic phase was dried(magnesium sulfate) and evaporated in vacuo. Silica gel chromatographyof the residue (5% 2M ammonia-methanol/dichloromethane) gave the titlecompound as a white solid (31 mg). ¹H NMR (400 MHz, CDCl₃): 6.91-6.87(m, 2H), 6.85-6.81 (m, 2H), 3.95 (t, J=6.4 Hz, 2H), 3.10 (t, J=4.9 Hz,4H), 2.69 (t, J=4.9 Hz, 4H), 2.48-2.44 (m, 2H), 2.39 (bs, 4H), 1.98-1.91(m, 2H), 1.61-1.56 (m, 4H), 1.46-1.40 (m, 2H), 1.09 (d, J=6.5 Hz, 6H).

Example 27

1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine

A solution of the product of Example 25 (151 mg), benzaldehyde (54 mg),and acetic acid (24 mg) in dichloroethane (3 mL) was treated with sodiumtriacetoxyborohydride (119 mg). After 14 h, the reaction was quenchedwith saturated aqueous sodium bicarbonate, and the aqueous phase wasextracted with dichloromethane (120 mL). The organic phase was dried(magnesium sulfate) and evaporated in vacuo. Silica gel chromatographyof the residue (5% 2M ammonia-methanol/dichloromethane) gave the titlecompound as an ivory solid (73 mg). ¹H NMR (400 MHz, CDCl₃): 7.36-7.24(m, 5H), 6.89-6.80 (m, 4H), 3.94 (t, J=6.4 Hz, 2H), 3.56 (s, 2H), 3.08(t, J=4.9 Hz, 4H), 2.61 (t, J=5.0 Hz, 4H), 2.48-2.44 (m, 2H), 2.39 (bs,4H), 1.98-1.91 (m, 2H), 1.61-1.56 (m, 4H), 1.46-1.40 (m, 2H).

Example 28

4-[3-(3-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine dihydrochloride

A solution of the product of Example 10 (1.0 g), piperidine (0.55 mL),and acetic acid (0.29 mL) in DCE (10 mL) was treated with sodiumtriacetoxyborohydride (1.5 g). After 16 h, saturated aqueous sodiumbicarbonate was added. The resulting mixture was extracted with DCM(3×10 mL). The combined organic phases were dried (magnesium sulfate)and evaporated, giving a material which was dissolved in n-butanol (20mL), treated with piperidine (0.65 mL), sodium carbonate (800 mg), andpotassium iodide (42 mg), and heated to 105° C. After 16 h, the reactionwas cooled to RT, treated with water (10 mL), and extracted with DCM(3×20 mL). The combined organic phases were dried (magnesium sulfate)and evaporated. The residue was treated with ether (20 mL), andfiltered. The filtrate was treated with hydrogen chloride (2.5 mL of a 2M solution in ether) followed by methanol (3 mL). The resulting solutionwas stirred for 1 h, and evaporated. Methanol (10 mL) was added, and theresulting suspension was heated to dissolve all solids. The mixture wascooled to RT, and ether (30 mL) was slowly added. Filtration gave thetitle compound as an amorphous white powder (0.74 g). ¹H NMR (400 MHz,MeOH-d₄): 7.19 (t, J=8.1 Hz, 1H), 6.89-6.87 (m, 2H), 6.79-6.76 (m, 1H),4.00 (t, J=6.4 Hz, 2H), 3.43 (s, 2H), 2.47 (d, J=7.6 Hz, 10H), 2.04-1.94(m, 2H), 1.62-1.54 (m, 8H), 1.45-1.42 (m, 4H).

Example 29

Dimethyl-{2-[4-(3-piperidin- 1-yl-propoxy)-phenoxy]-ethyl}-amine

A suspension of the product of Example 15 (217 mg),2-piperidylethan-1-ol (119 mg), and polymer-supported triphenylphosphine(613 mg, 3 mmol/g phosphorus content) in dichloromethane (4 mL) wastreated with a solution of di-tert-butyl azodicarboxylate (318 mg) indichloromethane (1 mL). The resulting mixture was stirred for 3 h andfiltered. Chromatography of the filtrate (2% 2Mammonia-methanol/dichloromethane) gave the title compound as a whitewaxy solid (58 mg). ¹H NMR (400 MHz, CDCl₃): 6.86-6.79 (m, 4H), 4.01 (t,J=5.7 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 2.70 (t, J=5.8 Hz, 2H), 2.51-2.37(m, 6H), 2.33 (s, 6H), 2.00-1.92 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.40(m, 2H).

Example 30

1-{3-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-propyl}-piperidine

A suspension of the product of Example 15 (217 mg),2-piperidylethan-1-ol (119 mg), and polymer-supported triphenylphosphine(613 mg, 3 mmol/g phosphorus content) in dichloromethane (4 mL) wastreated with a solution of di-tert-butyl azodicarboxylate (318 mg) indichloromethane (1 mL). The resulting mixture was stirred for 3 h andfiltered. Chromatography of the filtrate (2% 2Mammonia-methanol/dichloromethane) gave the title compound as a whitewaxy solid (58 mg). ¹H NMR (400 MHz, CDCl₃): 6.82 (s, 4H), 4.05 (t,J=6.2 Hz, 2H), 3.94 (t, J=6.5 Hz, 2H), 2.74 (t, J=6.2 Hz, 2H), 2.53-2.30(m, 10H), 1.99-1.90 (m, 2H), 1.64-1.55 (m, 8H), 1.49-1.39 (m, 4H).

Example 31

1-{3-[4-(3-Piperidin-1-yl-propoxy)-phenoxy]-propyl}-piperidine

A suspension of the product of Example 15 (132 mg),1-(3-hydroxypropyl)piperidine (132 mg), and polymer-supportedtriphenylphosphine (613 mg, 3 mmol/g phosphorus content) indichloromethane (4 mL) was treated with a solution of di-tert-butylazodicarboxylate (318 mg) in dichloromethane (1 mL). The resultingmixture was stirred for 3 h and filtered. Chromatography of the filtrate(2% 2M ammonia-methanol/dichloromethane) gave the title compound as awaxy solid (39 mg). ¹H NMR (400 MHz, CDCl₃): 6.81 (s, 4H), 3.94 (t,J=3.94, 4H), 2.49-2.34 (m, 12H), 1.99-1.90 (m, 4H), 1.63-1.55 (m, 8H),1.47-1.40 (m, 4H).

Example 32

1-(3-{4-[5-(3-Piperidin-1-yl-propylsulfanyl)-tetrazol-1-yl]-phenoxy}-propyl)-piperidine

A suspension of 1-(4-hydroxyphenyl)-1H-tetrazole-5-thiol (175 mg), theproduct of Example 1 (256 mg), and polymer-supported triphenylphosphine(600 mg, 3 mmol/g phosphorus content) in dichloromethane (5 mL) wastreated with di-tert-butyl azodicarboxylate (456 mg). The resultingmixture was stirred for 24 h and filtered. Chromatography of thefiltrate (5% 2M ammonia-methanol/dichloromethane) gave the titlecompound as a colorless oil (25 mg). ¹H NMR (400 MHz, CDCl₃): 7.40-7.35(m, 2H), 7.07-6.94 (m, 2H), 4.00 (t, J=6.4 Hz, 2H), 3.33 (t, J=7.1 Hz,2H), 2.43-2.40 (m, 2H), 2.36-2.29 (m, 10H), 1.97-1.89 (m, 4H), 1.56-1.46(m, 8H), 1.40-1.35 (m, 4H).

Example 33

5-(3-Piperidin-1-yl-propoxy)-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrimidine

A suspension of 2-(4-hyroxyphenyl)-5-pyrimidinol (169 mg), the productof Example 1 (256 mg), and polymer-supported triphenylphosphine (600 mg,3 mmol/g phosphorus content) in dichloromethane (5 mL) was treated withdi-tert-butyl azodicarboxylate (456 mg). The resulting mixture wasstirred for 24 h and filtered. Chromatography of the filtrate (5% 2Mammonia-methanol/dichloromethane) gave the title compound as a whitesolid (6.7 mg). ¹H NMR (400 MHz, CDCl₃): 8.24 (s, 2H), 8.06 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 4.10 (t, J=6.1 Hz, 2H), 3.82 (t, J=5.2Hz, 2H), 2.60-2.36 (m, 12H), 2.07-2. (m, 2H), 1.73-1.63 (m, 6H),1.61-1.55 (m, 4H), 1.48-1.44 (m, 4H). Example 34

1-[3-(2′-Piperidin-1-ylmethyl-biphenyl-4-yloxy)-propyl]-piperidine

The product of Example 16 (75 mg), was treated with 1 mL of a solutionprepared from piperidine (0.28 mL) and acetic acid (0.29 mL) indichloroethane (10 mL). The resulting solution was treated with sodiumtriacetoxyborohydride (68 mg). After 16 h, the reaction was quenchedwith saturated aqueous sodium bicarbonate, and the aqueous phase wasextracted with dichloromethane (3×1 mL). The combined organic phaseswere dried (magnesium sulfate) and evaporated in vacuo. Silica gelchromatography of the residue (4% 2M ammonia-methanol/dichloromethane)gave the title compound as a colorless oil (43 mg). ¹H NMR (400 MHz,CDCl₃): 7.52 (dd, J=6.9, 2.0 Hz, 1H), 7.34-7.20 (m, 5H), 6.92 (d, J=6.92Hz, 2H), 4.05 (t, J=4.5 Hz, 2H), 2.35 (s, 2H), 2.54-2.25 (m, 10H),2.06-1.98 (m, 2H), 1.64-1.35 (m, 12H).

Example 35

1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine

A solution of the product of Example 12 (6.13 g), piperidine (3.0 mL),sodium carbonate (3.6 g), and potassium iodide (190 mg) in n-butanol (50mL) was heated to 105° C. for 21 h, cooled to RT, and treated with water(50 mL). The resulting mixture was extracted with DCM (4×50 mL), and thecombined organic phases were dried (magnesium sulfate) and evaporated.Chromatography of the residue (5% 2M methanolic ammonia/methanol) gavethe title compound as a waxy solid (3.2 g). ¹H NMR (400 MHz, CDCl₃):7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.97 (t, J=6.5 Hz, 2H),3.4 (s, 2H), 2.48-2.31 (m, 1OH), 2.00-1.92 (m, 2H), 1.62-1.52 (m, 8H),1.47-1.38 (m, 4H).

Example 36

2-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-isoquinoline

A solution of the product of Example 11 (1.0 g),1,2,3,4-tetrahydro-isoquinoline (0.0.69 mL), and acetic acid (0.29 mL)in DCE (10 mL) was treated with sodium triacetoxyborohydride (1.5 g).After 16 h, saturated aqueous sodium bicarbonate was added. Theresulting mixture was extracted with DCM (3×10 mL). The combined organicphases were dried (magnesium sulfate) and evaporated, giving a materialwhich was dissolved in n-butanol (20 mL), treated with piperidine (0.65mL), sodium carbonate (800 mg), and potassium iodide (42 mg), and heatedto 105° C. After 16 h, the reaction was cooled to RT, treated with water(10 mL), and extracted with DCM (3×20 mL). The combined organic phaseswere dried (magnesium sulfate) and evaporated. The residue was treatedwith ether (20 mL), and filtered. The filtrate was treated with hydrogenchloride (2.5 mL of a 2 M solution in ether) followed by methanol (3mL). The resulting solution was stirred for 1 h, and evaporated. Theresidue was dried in vacuo, and ether was added, followed by enoughmethanol to cause a precipitate to form. Filtration gave the titlecompound as an amorphous pink powder (0.86 g). ¹H NMR (400 MHz, CDCl₃):7.27 (d, J=8.6 Hz, 2H), 7.13-7.05 (m, 4H), 6.99-6.96 (m,1H), 6.89-6.83(m, 2H), 4.00 (t, J=6.3 Hz, 2H), 3.60 (s, 4H), 2.89 (t, J=5.7 Hz, 2H),2.72 (t, J=5.8 Hz, 2H), 2.53-2.37 (m, 6H), 2.03-1.95 (m, 2H), 1.64-1.57(m, 4H), 1.49-1.40 (m, 2H).

Example 37

1-{3-[4-(1-Methyl-pyrrolidin-2-yl)-phenoxy]-propyl}-piperidine

The product of Example 5 (0.345 g) in diethylether (10 mL) was cooled to−78° C. and treated with n-butyllithium (0.5 mL, 2.5 M in hexane) andstirred at −78° C. for an additional 10 minutes whereupon the reactionmixture was warmed to 0° C. for 2-3 minutes then recooled to −78° C. Tothe cold solution was then added N-methylpyrrolidinone (0.099 g) and thereaction mixture warmed to ambient temperature. Separately a solution ofsodium borohydride (0.04 g) and trifluoroacetic acid (0.08 mL) indiethylether (5 mL) was prepared and the reaction mixture added to thissolution dropwise with rapid stirring. After 75 minutes the reactionmixture was treated with a solution of 20% sodium carbonate andextracted with ethyl acetate (3×25 mL). The organic extracts werecombined, dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel chromatography (4% methanolicammonia/DCM) to give the title compound (0.03 g). ¹H NMR (400 MHz,CDCl₃): 7.21(d, J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 3.98 (t, J=6.3,6.56 Hz, 2H), 3.20 (t, J=8.5 Hz, 1H), 2.95 (t, J=8.3 Hz, 1H), 2.17-2.57(m, 7H), 2.11 (s, 3H ), 1.95 (m, 3H), 1.74 ( m, 3H), 1.57 (m, 4H),1.37-1.48 (m, 2H).

Example 38

{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine

A solution of the product of Example 9 (30 mg),piperidin-4-yl-pyridin-2-yl-(2-pyrrolidin-1-yl-ethyl)-amine (29.8 mg),and acetic acid (0.015 mL) in DCM (1 mL) was treated with sodiumtriacetoxyborohydride (38 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-10% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (26 mg). ¹H NMR(400 MHz, CDCl₃): 8.12 (m, 1H), 7.39 (m, 1H), 7.21 (d, J=8.6 Hz, 2H),6.85 (d, J=8.6 Hz, 2H), 6.53-6.47 (m, 2H), 4.44 (m, 1H), 3.99 (t, J=6.3Hz, 2H), 3.51-3.47 (m, 2H), 3.46 (s, 2H), 2.95 (m, 2H), 2.62 (m, 6H),2.49 (m, 2H), 2.42 (m, 4H), 2.12 (m, 2H), 1.98 (m, 2H), 1.84-1.78 (m,5H), 1.75 (m, 1H), 1.68 (m, 2H), 1.63-1.57 (m, 4H), 1.44 (m, 2H).

Example 39

Pyridin-2-yl-[4-(3-pyrrolidin-1-yl-propoxy)-benzyl]-amine

A solution of 4-(3-Pyrrolidin-1-yl-propoxy)-benzaldehyde (0.51 g),2-aminopyridine (0.24 g), and acetic acid (0.13 mL) in DCM (7 mL) wastreated with sodium triacetoxyborohydride (650 mg). After 16 h, theresulting mixture was treated with 10% sodium hydroxide (10 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-4% 2 Mmethanolic ammonia/DCM) gave the title compound as an off white solid(500 mg). ¹H NMR (400 MHz, CDCl₃): 8.09 (m, 1H), 7.39 (m, 1H), 7.26 (d,J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.58 (m, 1H), 6.36 (m, 1H), 4.79(m, 1H), 4.41 (d, J=5.5, 2H), 4.01 (t, J=6.3 Hz, 2H), 2.63 (t, J=7.6 Hz,2H), 2.54 (m, 4H), 2.04-1.96 (m, 2H), 1.79 (m, 4H).

Example 40

Dimethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine

A suspension of 3-dimethylamino-1-propanol (0.178 mL), the product ofexample Example 17 (191 mg), polymer supported triphenyl phosphine (667mg; loading: 3 mmol/g) and di-tert-butylazodicarboxylate (345 mg) in DCM(15 mL) was shaken for 16 h. The resulting mixture was filtered througha pad of ceilite and washed with DCM (3×3 mL). The combined filtrateswere concentrated. Chromatography of the residue (1-6% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (90 mg). ¹H NMR(400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 4.00(d, J=6.5 Hz, 1H), 3.40 (s, 2H), 2.44 (t, J=7.4, 2H), 2.35 (bs, 4H),2.25 (s, 6H), 1.98-1.91 (m, 2H), 1.58-1.53 (m, 4H), 1.44-1.39 (m, 2H).

Example 41

{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-pyridin-2-yl-amine

A solution of the product of Example 9 (240 mg),piperidin-4-yl-pyridin-2-yl-amine (166 mg), and acetic acid (0.12 mL) inDCM (5 mL) was treated with sodium triacetoxyborohydride (290 mg). After16 h, the resulting mixture was treated with 10% sodium hydroxide (7 mL)and extracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (3% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (188mg). ¹H NMR (400 MHz, CDCl₃): 8.06 (m, 1H), 7.38 (m, 1H), 7.20 (d, J=8.8Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.53 (m, 1H), 6.34 (d, J=8.3 Hz, 1H),4.36 (br, m, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.60 (m, 1H), 3.45 (s, 2H),2.81 (m, 2H), 2.47 (m, 2H), 2.47 (br, 3H), 2.15 (m, 2H), 2.05-1.93 (m,4H), 1.62-1.54 (m, 4H), 1.50 (m, 1H), 1.44 (m, 2H).

Example 42

Methyl-phenethyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine

A solution of the product of Example 9 (152 mg),methyl-phenethyl-piperidin-4-yl-amine (128 mg), and acetic acid (0.11mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (190mg). After 16 h, the resulting mixture was treated with 10% sodiumhydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organicphases were dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (148 mg). ¹H NMR (400 MHz, CDCl₃): 7.29-7.25 (m, 2H),7.21-7.16 (m, 5H), 6.83 (j, J=8.6 Hz, 2H), 3.99 (d, J=6.3 Hz, 2H), 3.41(s, 2H), 2.92 (m, 2H), 2.77-2.66 (m, 4H), 2.47 (m, 2H), 2.40 (m, 4H),2.34 (s, 3H), 2.00-1.88 (m, 4H), 1.71 (m, 2H), 1.62-1.55 (m, 6H), 1.44(m, 2H).

Example 43

Benzyl-methyl-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-amine

A solution of the product of Example 9 (155 mg),benzyl-methyl-piperidin-4-yl-amine (123 mg), and acetic acid (0.11 mL)in DCM (3 mL) was treated with sodium triacetoxyborohydride (190 mg).After 16 h, the resulting mixture was treated with 10% sodium hydroxide(5 mL) and extracted with DCM (3×10 mL). The combined organic phaseswere dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (155 mg). ¹H NMR (400 MHz, CDCl₃): 7.31-7.28 (m, 4H),7.24-7.18 (m, 3H), 6.84 (d, J=8.8 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.56(s, 2H), 3.42 (s, 2H), 2.94 (m, 2H), 2.47 (m, 2H), 2.40 (m, 4H), 2.19(s, 3H), 2.01-1.88 (m, 4H), 1.77 (m, 2H), 1.67 (m, 2H), 1.59 (m, 4H),1.44 (m, 2H)

Example 44

1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-decadeuterio-piperidine

A suspension of the product of Example 12 (1.0 g), perdeuteropiperidine(0.58 mL), sodium carbonate (3.6 g), and potassium iodide (30 mg) in1-butanol (15 mL) was heated to 105° C. for 16 h, cooled to RT, dilutedwith water (6 mL) and extracted with DCM (3×12 mL). The combined organicphases were dried (magnesium sulfate) and evaporated. Chromatography ofthe residue (3% 2 M methanolic ammonia/DCM) gave the title compound as ayellow oil (872 mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.2 Hz, 2H),6.84 (d, J=8.4 Hz, 2H), 3.98 (t, J=6.5 Hz, 2H), 3.41 (s, 2H), 2.46 (t,J=7.4 Hz, 2H), 2.38-2.28 (br s, 4H), 2.00-1.92 (m, 2H), 1.59-1.50 (m,4H), 1.45-1.34 (m, 2H).

Example 45

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-azacyclotridecane

A solution of the product of Example 9 (175 mg), dodecamethyleneamine(143 mg), and acetic acid (0.09 mL) in DCE (3 mL) was treated withsodium triacetoxyborohydride (210 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (3% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (140 mg). ¹H NMR(400 MHz, CDCl₃): 7.20 (d, J=8.8 Hz 2H), 6.82 (d, J=8.6 Hz, 2H), 3.99(t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.50-2.31 (m, 10H), 2.01-1.93 (m, 2H),1.63-1.56 (m, 4H), 1.48-1.34 (m, 22H).

Example 46

2-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-ethanol

A solution of the product of Example 9 (175 mg),4-hydroxyethylpiperidine (101 mg), (143 mg), and acetic acid (0.02 mL)in DCE (3 mL) was treated with sodium triacetoxyborohydride (210 mg).After 16 h, the resulting mixture was treated with 10% sodium hydroxide(1 mL) and extracted with DCM (3×3 mL). The combined organic phases weredried (magnesium sulfate) and evaporated. Chromatography of the residue(3% 2 M methanolic ammonia/DCM) gave the title compound as a colorlessoil (80 mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d,J=8.6 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.65 (t, J=6.7 Hz, 2H), 3.41 (s,2H), 2.88-2.82 (m, 2H), 2.50-2.33 (m, 7H), 2.01-1.86 (m, 4H), 1.68-1.55(m, 6H), 1.52-1.37 (m, 5H), 1.31-1.20 (m, 2H).

Example 47

Indan-1-yl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (175 mg), 1-aminoindane (0.10mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (119 mg). ¹H NMR(400 MHz, CDCl₃): 7.37-7.34 (m, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.25-7.17(m, 3H), 6.86 (d, J=8.8 Hz, 2H), 4.28 (t, J=6.7 Hz, 1H), 3.99 (t, J=6.5Hz, 2H), 3.86 (d, J=13 Hz,1H), 3.81 (d, J=13 Hz, 1H), 3.05-2.96 (m, 1H),2.85-2.76 (m,1H), 2.49-2.36 (m, 6H), 2.00-1.82 (m, 3H), 1.62-1.55 (m,4H), 1.47-1.39 (m, 2H)

Example 48

1-[3-(4-Pyrrolidin-1-ylmethyl-phenoxy)-propyl]-piperidine

A solution of the product of Example 9 (175 mg), pyrrolidine (0.07 mL),and acetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (3% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (27 mg). ¹H NMR(400 MHz, CDCl₃): 7.21 (d, J=8.6 Hz, 2H), 7.0 (d, J=8.8 Hz, 2H), 3.99(t, J=6.3 Hz, 2H), 3.52 (s, 2H), 2.50-2.32 (m,1 OH), 2.01-1.92 (m, 2H),1.79-1.72 (m, 4H), 1.61-1.54 (m, 4H), 1.49-1.40 (m, 2H).

Example 49

Cyclohexyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (175 mg), aminocyclohexane (0.09mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (84 mg). ¹H NMR(400 MHz, CDCl₃): 7.21 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 3.98(t, J=6.5 Hz, 2H), 3.73 (s, 2H), 2.50-2.35 (m, 7H), 2.00-1.86 (m, 4H),1.76-1.68 (m, 2H), 1.64-1.55 (m, 5H), 1.47-1.39 (m, 2H), 1.30-1.04 (m,5H).

Example 50

Cyclopropyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (175 mg), aminocyclopropane (0.05mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (4% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (113 mg). ¹H NMR(400 MHz, CDCl₃): 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 3.98(t, J=6.5 Hz, 2H), 3.76 (s, 2H), 2.49-2.35 (m, 6H), 2.16-2.09 (m, 1H),2.00-1.92 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.39 (m, 2H), 0.45-0.34 (m,4H).

Example 51

4-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-morpholine

A suspension of the product of Example 12 (268 mg), morpholine (0.11mL), sodium carbonate (159 g), and potassium iodide (8.3 mg) in1-butanol (4 mL) was heated to 105 C for 16 h, cooled to RT, dilutedwith water (2 mL) and extracted with DCM (3×3 mL). The combined organicphases were dried (magnesium sulfate) and evaporated. Chromatography ofthe residue (2.5% 2 M methanolic ammonia/DCM) gave the title compound asa yellow oil (93 mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H),6.84 (d, J=8.8 Hz, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.72 (t, J=4.5 Hz, 4H),3.40 (s, 2H), 2.54-2.44 (m, 6H), 2.34 (br s, 4H), 1.99-1.92 (m, 2H),1.58-1.52 (m, 4H), 1.45-1.38 (m, 2H).

Example 52

1-Methyl-4-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperazine

A suspension of the product of Example 12 (268 mg), N-methylpiperazine(0.14 mL), sodium carbonate (159 g), and potassium iodide (8.3 mg) in1-butanol (4 mL) was heated to 105° C. for 16 h, cooled to RT, dilutedwith water (2 mL) and extracted with DCM (3×3 mL). The combined organicphases were dried (magnesium sulfate) and evaporated. Chromatography ofthe residue (4% 2 M methanolic ammonia/DCM) gave the title compound as ayellow oil (86 mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H),6.81 (d, J=8.6 Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.40 (s, 2H), 2.53-2.30(m, 14H), 2.28 (s, 3H), 2.00-1.91 (m, 2H), 1.59-1.50 (m, 4H), 1.44-1.38(m, 2H).

Example 53

1-Methyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine

A solution of the product of Example 9 (175 mg), N-methylpiperazine(0.09 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated withsodium triacetoxyborohydride (210 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (4% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (79 mg). ¹H NMR(400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 3.97(t, J=6.3 Hz, 2H), 3.43 (s, 2H), 2.50-2.35 (m, 14H), 2.28 (s, 3H),2.00-1.93 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).

Example 54

8-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,4-dioxa-8-aza-spiro[4.5]decane

A solution of the product of Example 9 (175 mg),1,4-dioxa-8-azaspiro[4.5]-decane (112 mg), and acetic acid (0.01 mL) inDCE (3 mL) was treated with sodium triacetoxyborohydride (210 mg). After16 h, the resulting mixture was treated with 10% sodium hydroxide (1 mL)and extracted with DCM (3×3 mL). The combined organic phases were dried(magnesium sulfate) and evaporated. Chromatography of the residue (2.5%2 M methanolic ammonia/DCM) gave the title compound as a colorless oil(68 mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6Hz, 2H), 3.98 (t, J=6.5 Hz, 2H), 3.94 (s, 4H), 3.45 (s, 2H), 2.53-2.35(m, 10H), 2.00-1.92 (m, 2H), 1.75-1.71 (m, 4H), 1.62-1.55 (m, 4H),1.47-1.39 (m, 2H).

Example 55

2-(4-Chloro-phenyl)-5-[4-(3-piperidin-1-yl-propoxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane

A solution of the product of Example 9 (175 mg),2-phenyl-2,5-diaza-bicyclo[2.2.1]heptane hydrobromide(162 mg), andacetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (111 mg). ¹H NMR(400 MHz, CDCl₃): 7.19 (d, J=8.8 Hz, 2H), 7.14 (d, J=9.0 Hz, 2H), 6.82(d, J=8.6 Hz, 2H), 6.47 (d, J=9.0 H2, 2H), 4.15 (brs, 1H), 3.97 (t,J=6.5 Hz, 2H), 3.59 (s, 2H), 3.52 (brs, 1H), 3.35 (dd, J=8.8, 2.2 Hz,1H), 3.27 (dd, J=9.0 Hz, 0.8 Hz, 1H), 2.89 (dd, J=9.6, 2.0 Hz, 1H), 2.63(dd, J=9.6, 1.1 Hz, 1H), 2.48-2.35 (m, 5H), 2.05-1.83 (m, 5H), 1.62-1.54(m, 4H), 1.47-1.39 (m, 2H).

Example 56

1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one

A solution of the product of Example 9 (175 mg),1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (170 mg), and aceticacid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (111 mg). ¹H NMR(400 MHz, CDCl₃): 10.47 (br s,1H), 7.30-7.23 (m, 3H), 7.12-7.01 (m, 3H),6.86 (d, J=8.8 Hz, 2H), 4.42-4.32 (m, 1H), 4.00 (t, J=6.5 Hz, 2H), 3.51(s, 2H), 3.07-3.01 (m, 2H), 2.52-2.30 (m, 8H), 2.15 (dd, J=12, 12 Hz,2H), 2.02-1.94 (m, 2H), 1.83-1.76 (m, 2H), 1.64-1.55 (m, 4H), 1.48-1.40(m, 2H).

Example 57

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidine-4-carboxylic acidamide

A solution of the product of Example 9 (175 mg), piperidine-4-carboxylicacid amide (100 mg), and acetic acid (0.1 mL) in DCE (3 mL) was treatedwith sodium triacetoxyborohydride (210 mg). After 16 h, the resultingmixture was treated with 10% sodium hydroxide (1 mL) and extracted withDCM (3×3 mL). The combined organic phases were dried (magnesium sulfate)and evaporated. Chromatography of the residue (5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (84 mg). ¹H NMR(400 MHz, CDCl₃): 7.19 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.6 Hz, 1H), 5.91(br s, 1H), 5.61 (br s,1H), 3.99 (t, J=6.4 Hz, 2H), 3.42 (s, 2H),2.94-2.88 (m, 2H), 2.49-2.35 (m, 6H), 2.17-2.08 (m, 1H), 2.01-1.91 (m,4H), 1.87 -1.67 (m, 4H), 1.62-1.55 (m, 4H), 1.47-1.40 (m, 2H).

Example 58

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-4-(3-phenyl-propyl)-piperidine

A solution of the product of Example 9 (175 mg),4-(3-phenyl-propyl)-piperidine (158 mg), and acetic acid (0.09 mL) inDCE (3 mL) was treated with sodium triacetoxyborohydride (210 mg). After16 h, the resulting mixture was treated with 10% sodium hydroxide (1 mL)and extracted with DCM (3×3 mL). The combined organic phases were dried(magnesium sulfate) and evaporated. Chromatography of the residue (2% 2M methanolic ammonia/DCM) gave the title compound as a colorless oil(107 mg). ¹H NMR (400 MHz, CDCl₃): 7.28-7.13 (m, 7H), 6.82 (d, J=8.6 Hz,2H), 3.97 (t, J=6.3 Hz, 2H), 3.40 (s, 2H), 2.87-2.81 (m, 2H), 2.57 (dd,J=7.7, 7.7 Hz, 2H), 2.49-2.35 (m, 6H), 2.00-1.82 (m, 4H), 1.66-1.55 (m,8H), 1.47-1.39 (m, 2H), 1.30-1.16 (m, 5H).

Example 59

Dimethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (175 mg), dimethylaminehydrochloride (64 mg), and acetic acid (0.05 mL) in DCE (3 mL) wastreated with sodium triacetoxyborohydride (210 mg). After 16 h, theresulting mixture was treated with 10% sodium hydroxide (1 mL) andextracted with DCM (3×3 mL). The combined organic phases were dried(magnesium sulfate) and evaporated. Chromatography of the residue (3% 2M methanolic ammonia/DCM) gave the title compound as a colorless oil (70mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz,2H), 3.99 (t, J=6.4 Hz, 2H), 3.35 (s, 2H), 2.50-2.35 (m, 6H), 2.22 (s,6H), 2.01-1.94 (m, 2H), 1.63-1.55 (m, 4H), 1.46-1.40 (m, 2H).

Example 60

1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-1H-benzoimidazole

A solution of the product of Example 9 (82 mg),1-Piperidin-4-yl-1H-benzoimidazole (62 mg), and acetic acid (0.03 mL) inDCM (3 mL) was treated with sodium triacetoxyborohydride (110 mg). After16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL)and extracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (81mg). ¹H NMR (400 MHz, CDCl₃): 7.98 (s, 1H), 7.80 (m, 1H), 7.42 (m, 1H),7.30-7.20 (m, 4H), 6.87 (d, J=8.6 Hz, 2H), 4.18 (m, 1H), 4.00 (t, J=6.3Hz, 2H), 3.52 (s, 2H), 3.10-3.03 (m, 2H), 2.48 (m, 2H), 2.41 (br, 4H),2.21-2.10 (m, 5H), 2.01-1.94 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.39 (m,2H).

Example 61

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl

A solution of the product of Example 9 (174 mg),1,2,3,4,5,6-hexahydro-[2,3′]bipyridinyl (111 mg), and acetic acid (0.05mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (240mg). After 16 h, the resulting mixture was treated with 10% sodiumhydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organicphases were dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (112 mg). ¹H NMR (400 MHz, CDCl₃): 8.63 (m, 1H), 8.49 (m,1H), 7.80 (m, 1H), 7.27 (m, 1H), 7.11 (d, J=8.6 Hz, 2H) 6.80 (d, J=8.6Hz, 2H), 3.97 (t, J=6.3 Hz, 2H), 3.61 (d, J=13.4 Hz, 1H), 3.13 (m, 1H),2.97 (m, 1H), 2.79 (d, J=13.4 Hz, 1H), 2.48 (m, 2H), 2.41 (br, 4H),2.01-1.98 (m, 5H), 2.01-1.89 (m, 3H), 1.82-1.72 (m, 2H) 1.63-1.51 (m,4H), 1.48-1.39 (m, 2H).

Example 62

Phenyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (277 mg), aniline (108 mg), andacetic acid (0.07 mL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (340 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (256 mg). ¹H NMR(400 MHz, CDCl₃): 7.27 (m, 2H), 7.18 (m, 2H), 6.88 (m, 2H), 6.72 (m,2H), 6.64 (m, 2H), 4.24 (s, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.94 (br,1H),2.48 (m, 2H), 2.41 (br, 4H), 1.98 (m, 2H), 1.64-1.57 (m, 4H), 1.48-1.41(m, 2H).

Example 63

5-Bromo-1-{1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole

A solution of the product of Example 9 (93 mg) and5-bromo-1-piperidin-4-yl-2,3-dihydro-1H-indole*2 TFA (191 mg) in DCM (2mL) was treated with sodium triacetoxyborohydride (150 mg). After 16 h,the resulting mixture was treated with 10% sodium hydroxide (5 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (79mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 7.11-7.07 (m, 2H),6.84 (d, J=8.6 Hz, 2H), 6.23 (d, J=9.1 Hz, 1H), 4.00 (t, J=6.1 Hz, 2H),3.46 (s, 2H), 3.37 (7, J=8.3 Hz, 2H), 3.28 (m, 1H), 2.97 (m, 2H), 2.90(t, J=8.3 Hz, 2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.06-1.97 (m, 4H),1.75-1.60 (m, 8H), 1.50-1.43 (m, 2H).

Example 64

1-{1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-yl}-2,3-dihydro-1H-indole

A solution of the product of Example 9 (112 mg) and1-piperidin-4-yl-2,3-dihydro-1H-indole*2TFA (194 mg) in DCM (2 mL) wastreated with sodium triacetoxyborohydride (150 mg). After 16 h, theresulting mixture was treated with 10% sodium hydroxide (5 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (78mg). ¹H NMR (400 MHz, CDCl₃): 7.22 (d, J=8.6 Hz, 2H), 7.06-7.00 (m, 2H),6.85 (d, J=8.6 Hz, 2H), 6.59 (t, J=7.1 Hz, 1H), 6.39(d, J=7.8 Hz, 1H),4.00 (t, J=6.3 Hz, 2H), 3.48 (s, 2H), 3.41-3.32 (m, 3H), 2.99 (m, 2H),2.93 (t, J=8.3 Hz, 2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.09-1.98 (m, 4H),1.79-1.70 (m, 4H), 1.67-1.61 (m, 4H), 1.50-1.43 (m, 2H).

Example 65

[2-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine

A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (269 mg),2-aminopyridine (110 mg), and acetic acid (0.07 mL) in DCM (5 mL) wastreated with sodium triacetoxyborohydride (410 mg). After 16 h, theresulting mixture was treated with 10% sodium hydroxide (6 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (128mg). ¹H NMR (400 MHz, CDCl₃): 8.07 (m, 1H), 7.37 (m, 1H), 7.29 (m, 1H),7.22 (m, 1H), 6.91-6.84 (m, 2H), 6.54 (m, 1H), 6.37 (m, 1H), 5.00 (m,1H), 4.48 (d, J=5.6, 2H), 4.04 (t, J=6.3 Hz, 2H), 2.52 (m, 2H), 2.41(br, 4H), 2.02 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.40 (m, 2H).

Example 66

[3-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine

A solution of the product of Example 13 (262 mg), 2-aminopyridine (104mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (410 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (6 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (114 mg). ¹H NMR(400 MHz, CDCl₃): 8.10 (m, 1H), 7.39 (m, 1H), 7.22 (m, 1H), 6.94-6.89(m, 2H), 6.79 (m, 1H), 6.58 (m, 1H), 6.36 (m, 1H), 4.89 (m, 1H), 4.46(d, J=5.6, 2H), 3.98 (t, J=6.3 Hz, 2H), 2.47 (m, 2H), 2.41 (br, 4H),1.97 (m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 67

(4-Chloro-phenyl)-[2-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (266 mg),4-chloroaniline (146 mg), and acetic acid (0.07 mL) in DCM (5 mL) wastreated with sodium triacetoxyborohydride (400 mg). After 16 h, theresulting mixture was treated with 10% sodium hydroxide (6 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (246mg). ¹H NMR (400 MHz, CDCl₃): 7.28-7.20 (m, 2H), 7.09 (d, J=8.9 Hz, 2H),6.89 (m, 2H), 6.55 (d, J=8.9 Hz, 2H), 4.30 (d, J=5.6, 2H), 4.18 (m, 1H),4.05 (t, J=6.3 Hz, 2H), 2.47 (m, 2H), 2.37 (br, 4H), 1.96 (m, 2H),1.62-1.56 (m, 4H), 1.49-1.42 (m, 2H).

Example 68

(4-Chloro-phenyl)-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 13 (268 mg), 4-chloroaniline (145mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (400 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (6 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (154 mg). ¹H NMR(400 MHz, CDCl₃): 7.24 (m, 2H),7.10 (d, J=8.9 Hz, 2H), 6.93-6.88 (m,2H), 6.81 (m, 1H), 6.54 (d, J=8.9 Hz, 2H), 4.26 (d, J=5.6, 2H), 4.07 (m,1H), 3.99 (t, J=6.3 Hz, 2H), 2.46 (m, 2H), 2.40 (br, 4H), 1.96 (m, 2H),1.62-1.56 (m, 4H), 1.49-1.42 (m, 2H).

Example 69

2-{1-[3-(4-Piperidin-1-ylmethyl-phenoxy)-propyl]-piperidin-2-yl}-ethanol

A suspension of the product of Example 12 (268 mg),2-hydroxyethylpiperidine (168 mg), sodium carbonate (159 g), andpotassium iodide (8.3 mg) in 1-butanol (4 mL) was heated to 105° C. for16 h, cooled to RT, diluted with water (2 mL) and extracted with DCM(3×5 mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (4% 2 M methanolicammonia/DCM) gave the title compound as a colorless glassy solid (53mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz,2H), 3.97 (t, J=6.3 Hz, 2H), 3.91-3.84 (m,1H), 3.78-3.71 (m, 1H), 3.40(s, 2H), 3.10-2.94 (m, 2H), 2.74-2.64 (m, 2H), 2.39-2.31 (m, 5H),2.02-1.86 (m, 3H), 1.75-1.35 (m,14H).

Example 70

1-{3-[2-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine

A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (212 mg),4-benzylidene-piperidine (154 mg), and acetic acid (0.05 mL) in DCM (3mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h,the resulting mixture was treated with 10% sodium hydroxide (6 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (148mg). ¹H NMR (400 MHz, CDCl₃): 7.37 (m, 1H), 7.30 (m, 2H), 7.23-7.16 (m,4H), 6.92 (m, 1H), 6.86 (m, 1H), 6.27 (s, 1H), 4.00 (t, J=6.3 Hz, 2H),3.60 (s, 2H), 2.60 (m, 2H), 2.55-2.46 (m, 6H), 2.44-2.37 (m, 6H), 2.00(m, 2H), 1.64-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 71

1-{3-[3-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine

A solution of the product of Example 13 (210 mg),4-Benzylidene-piperidine (153 mg), and acetic acid (0.05 mL) in DCM (3mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h,the resulting mixture was treated with 10% sodium hydroxide (6 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (189mg). ¹H NMR (400 MHz, CDCl₃): 7.30 (m, 2H), 7.23-7.16 (m, 3H), 6.89 (m,2H), 6.79 (m, 1H), 6.27 (s, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.49 (s, 2H),2.55-2.46 (m, 6H), 2.45-2.37 (m, 6H), 1.99 (m, 2H), 1.64-1.56 (m, 4H),1.47-1.40 (m, 2H).

Example 72

1-{3-[4-(4-Benzylidene-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine

A solution of the product of Example 9 (204 mg),4-Benzylidene-piperidine (145 mg), and acetic acid (0.05 mL) in DCM (3mL) was treated with sodium triacetoxyborohydride (300 mg). After 16 h,the resulting mixture was treated with 10% sodium hydroxide (5 mL) andextracted with DCM (3×10 mL). The combined organic phases were dried(magnesium sulfate) and evaporated. Chromatography of the residue (1 to5% 2 M methanolic ammonia/DCM) gave the title compound as a colorlessoil (308 mg). ¹H NMR (400 MHz, CDCl₃): 7.30 (m, 2H), 7.24-7.16 (m, 4H),6.84 (m, 2H), 6.26 (s,1H), 3.99 (t, J=6.3 Hz, 2H), 3.46 (s, 2H),2.54-2.44 (m, 6H), 2.43-2.35 (m, 6H), 1.97 (m, 2H), 1.74 (br, 1H),1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 73

2-Methyl-1-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-piperidine

A suspension of the product of Example 17 (176 mg),3-(2-methyl-piperidin-1-yl)-propan-1-ol (145 mg), and polymer supportedtriphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treatedwith di-tert-butylazodicarboxylate (316 mg). After 2 h, the resultingmixture was filtered, and the filtrate was evaporated. Chromatography ofthe residue (2.5% 2 M methanolic ammonia/DCM) gave the title compound asa colorless oil (60 mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz,2H), 6.83 (d, J=8.6 Hz, 2H), 4.01-3.92 (m, 2H), 3.40 (s, 2H), 2.90-2.81(m, 2H), 2.56-2.47 (m, 1H), 2.40-2.25 (m, 5H), 2.21-2.14 (m, 1H),1.97-1.88 (m, 2H), 1.70-1.51 (m, 8H), 1.45-1.25 (m, 4H), 1.07 (d, J=6.2Hz, 3H).

Example 74

Methyl-phenethyl-[3-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 13 (103 mg), methyl-phenethyl-amine(56 mg), and acetic acid (0.03 mL) in DCM (2 mL) was treated with sodiumtriacetoxyborohydride (150 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (26 mg). ¹H NMR(400 MHz, CDCl₃): 7.30-7.25 (m, 2H), 7.22-7.16 (m, 4H), 6.87-6.84 (m,2H), 6.78 (m,1H), 3.97 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 2.82 (m, 2H),2.64 (m, 2H), 2.48 (m, 2H), 2.40 (br, 4H), 2.28 (s, 3H), 1.97 (m, 2H),1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 75

1-(3-Phenyl-allyl)-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine

A solution of the product of Example 9 (215 mg),1-(3-phenyl-allyl)-piperazine (176 mg), and acetic acid (0.06 mL) in DCM(3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16h, the resulting mixture was treated with 10% sodium hydroxide (5 mL)and extracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (303mg). ¹H NMR (400 MHz, CDCl₃): 7.36 (m, 2H), 7.30 (m, 2H), 7.24-7.18 (m,3H), 6.83 (d, J=8.6 Hz, 2H), 6.51 (d, J=15.9 Hz, 1H), 6.31-6.23 (m, 1H),3.98 (t, J=6.3 Hz, 2H), 3.45 (s, 2H), 3.15 (m, 2H), 2.60-2.32 (m, 12H),1.67 (br, 1H), 1.62-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 76

Methyl-(1-methyl-piperidin-4-yl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (227 mg),methyl-(1-methyl-piperidin-4-yl)-amine (118 mg), and acetic acid (0.06mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290mg). After 16 h, the resulting mixture was treated with 10% sodiumhydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organicphases were dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (270 mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H),6.83 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.49 (s, 2H), 2.90 (m,2H), 2.78 (m, 2H), 2.46 (m, 2H), 2.43-2.35 (m, 4H), 2.26 (s, 3H), 2.17(s, 3H), 2.00-1.87 (m, 5H), 1.78 (m, 2H), 1.68 (m, 2H), 1.61-1.54 (m,4H), 1.47-1.40 (m, 2H).

Example 77

1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperidin-4-ol

A solution of the product of Example 5 (297 mg) in THF (2 mL) was cooledin a −78° C. bath and treated with a 1.6 M solution of butyllithium inhexanes (0.69 mL). After 1 h, a solution of 1-benzyl-piperidin-4-one(0.19 mL) in THF (1 mL) was added, and the mixture was allowed to warmto RT. After 1 h, water (2 mL) was added. The mixture was extracted withether (2×2 mL), and the combined organic phases were dried (magnesiumsulfate), and evaporated. Chromatography of the residue (3% 2 Mmethanolic ammonia/DCM) gave the title compound as an amorphous whitesolid (94 mg). ¹H NMR (400 MHz, CDCl₃): 7.42 (d, J=9.0 Hz, 2H), 6.87 (d,J=9.0 Hz, 2H), 3.99 (t, J=6.5 Hz, 2H), 2.82-2.74 (m, 3H), 2.66-2.58 (m,2H), 2.48-2.34 (m, 5H), 2.18-2.08 (m, 2H), 2.01-1.74 (m, 5H), 1.63-1.52(m, 5H), 1.47-1.39 (m, 2H), 1.10 (d, J=6.7Hz, 6H).

Example 78

Methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-(2-pyridin-2-yl-ethyl)-amine

A solution of the product of Example 9 (256 mg),methyl-(2-pyridin-2-yl-ethyl)-amine (143 mg), and acetic acid (0.06 mL)in DCM (4 mL) was treated with sodium triacetoxyborohydride (330 mg).After 16 h, the resulting mixture was treated with 10% sodium hydroxide(5 mL) and extracted with DCM (3×10 mL). The combined organic phaseswere dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (325 mg). ¹H NMR (400 MHz, CDCl₃): 8.51 (m, 1H), 7.57 (m,1H), 7.18-7.12 (m, 3H),7.10 (m, 1H), 6.82 (d, J=8.6 Hz, 2H), 3.98 (t,J=6.3 Hz, 2H), 3.49 (s, 2H), 2.99 (m, 2H), 2.78 (m, 2H), 2.46 (m, 2H),2.39 (br, 4H), 2.25 (s, 3H), 2.96 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.40(m, 2H).

Example 79

Ethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-pyridin-4-ylmethyl-amine

A solution of the product of Example 9 (222 mg)ethyl-pyridin-4-ylmethyl-amine (122 mg), and acetic acid (0.06 mL) inDCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL)and extracted with DCM (3×10 mL). The combined organic phases were dried(sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 Mmethanolic ammonia/DCM) gave the title compound as a colorless oil (246mg). ¹H NMR (400 MHz, CDCl₃): 8.51 (m, 2H), 7.29 (m, 2H), 7.24 (m, 2H),6.84 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.52 (s, 2H), 3.50 (s,2H), 2.51-2.44 (m, 4H), 2.40 (br, 4H), 1.97 (m, 2H), 1.62-1.55 (m, 4H),1.47-1.40 (m, 2H), 1.06 (t, J=7.0 Hz, 3H).

Example 80

Benzyl-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (218 mg), benzyl methylamine (108mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodiumtriacetoxyborohydride (300 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (269 mg). ¹H NMR(400 MHz, CDCl₃): 7.37-7.28 (m, 4H), 7.27-7.22 (m, 5H), 6.85 (d, J=8.6Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.49 (s, 2H), 3.45 (s, 2H), 2.50-2.31(m, 6H), 2.16 (s, 3H), 1.97 (m, 2H), 1.62-1.55 (m, 4H), 1.47-1.40 (m,2H).

Example 81

Diethyl-[2-(4-piperidin-1-ylmethyl-phenoxy)-ethyl]-amine

A suspension of the product of Example 17 (176 mg),2-Diethylamino-ethanol (0.12 mL), and polymer supportedtriphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treatedwith di-tert-butylazodicarboxylate (316 mg). After 2 h, the resultingmixture was filtered, and the filtrate was evaporated. Chromatography ofthe residue (3% 2 M methanolic ammonia/DCM) gave the title compound as apale yellow oil (37 mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.8 Hz,2H), 6.84 (d, J=8.6 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.40 (s, 2H), 2.87(t, J=6.5 Hz, 2H), 2.63 (q, J=7.0 Hz, 4H), 2.35 (br s, 4H), 1.59-1.52(m, 4H), 1.46-1.37 (m, 2H), 1.07 (t, J=7.1 Hz, 6H).

Example 82

[2-(3,4-Dimethoxy-phenyl)-ethyl]-methyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (214 mg),[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amine (170 mg), and acetic acid(0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride(300 mg). After 16 h, the resulting mixture was treated with 10% sodiumhydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organicphases were dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (350 mg). ¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.6 Hz, 2H),6.85-6.69 (m, 5H), 3.99 (t, J=6.3 Hz, 2H), 3.85 (s, 6H), 3.48 (s, 2H),2.79-2.74 (m, 2H), 2.63-2.58 (m, 2H), 2.50-2.35 (m, 6H), 2.25 (s, 3H),1.97 (m, 2H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 83

Methyl-phenethyl-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (208 mg), methyl-phenethyl-amine(113 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated withsodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (5 mL) and extracted with DCM(3×10 mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (300 mg). ¹H NMR(400 MHz, CDCl₃): 7.30-7.25 (m, 2H), 7.21-7.16 (m, 5H), 6.83 (d, J=8.6Hz, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.49 (s, 2H),2.84-2.79 (m, 2H),2.65-2.62 (m, 2H), 2.51-2.37 (m, 6H), 2.26 (s, 3H), 1.98 (m, 2H),1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).

Example 84

[4-(3-Piperidin-1-yl-propoxy)-benzyl]-pyridin-2-yl-amine

A solution of the product of Example 9 (0.51 g), 2-aminopyridine (0.24g), and acetic acid (0.12 mL) in DCM (7 mL) was treated with sodiumtriacetoxyborohydride (650 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-4% 2 M methanolicammonia/DCM) gave the title compound as an off white solid (440 mg). ¹HNMR (400 MHz, CDCl₃): 8.05 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.6 Hz,2H), 6.83 (d, J=8.6 Hz, 2H), 6.53 (m, 1H), 6.32 (m, 1H), 5.05 (m, 1H),4.37 (d, J=5.6, 2H), 3.95 (t, J=6.3 Hz, 2H), 2.44 (m, 2H), 2.37 (br,4H), 1.94 (m, 2H), 1.59-1.53 (m, 4H), 1.45-1.38 (m, 2H).

Example 85

(4-Chloro-phenyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine

A solution of the product of Example 9 (260 mg), 4-chloroaniline (180mg), and acetic acid (0.06 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (360 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (168 mg). ¹H NMR(400 MHz, CDCl₃): 7.25 (d, J=8.8 Hz, 2H),7.10 (d, J=8.9 Hz, 2H), 6.87(d, J=8.8 Hz, 2H), 6.54 (d, J=8.9 Hz, 2H), 4.21 (d, J=4.7, 2H), 3.99 (t,J=6.3 Hz, 2H), 2.52-2.38 (m, 6H), 1.99 (m, 2H), 1.64-1.57 (m, 4H),1.49-1.42 (m, 2H).

Example 86

4-(4-Chloro-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol

A solution of the product of Example 9 (200 mg),4-(4-chloro-phenyl)-piperidin-4-ol (170 mg), and acetic acid (0.05 mL)in DCM (3 mL) was treated with sodium triacetoxyborohydride (300 mg).After 16 h, the resulting mixture was treated with 10% sodium hydroxide(5 mL) and extracted with DCM (3×10 mL). The combined organic phaseswere dried (sodium sulfate) and evaporated. Chromatography of theresidue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as acolorless oil (203 mg). ¹H NMR (400 MHz, CDCl₃): 7.46-7.42 (m, 2H),7.32-7.28 (m, 2H), 7.25-7.22 (m, 2H), 6.87-6.84 (m, 2H), 3.99 (t, J=6.3Hz, 2H), 3.51 (s, 2H), 2.78 (m, 2H), 2.51-2.36 (m, 8H), 2.11 (m, 2H),1.98 (m, 2H), 1.69 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.40 (m, 2H).

Example 87

4-Phenyl-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol

A solution of the product of Example 9 (210 mg), 4-Phenyl-piperidin-4-ol(150 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated withsodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (5 mL) and extracted with DCM(3×10 mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (225 mg). ¹H NMR(400 MHz, CDCl₃): 7.54-7.49 (m, 2H), 7.37-7.33 (m, 2H), 7.28-7.23 (m,3H), 6.88-6.84 (m, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.51 (s, 2H), 2.78 (m,2H), 2.50-2.36 (m, 8H), 2.15 (m, 2H), 1.97 (m, 2H), 1.73 (m, 2H),1.63-1.55 (m, 4H), 1.47-1.40 (m, 2H).

Example 88

1-Isopropyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine

A solution of the product of Example 9 (200 mg), 1-isopropyl-piperazine(100 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated withsodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (5 mL) and extracted with DCM(3×10 mL). The combined organic phases were dried (sodium sulfate) andevaporated. Chromatography of the residue (1-5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (225 mg). ¹H NMR(400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 3.98(t, J=6.6 Hz, 2H), 3.43 (s, 2H), 2.63 (m, 1H), 2.53 (br, 4H), 2.46 (m,4H), 2.39 (br, 4H), 1.96 (m, 2H), 1.58 (m, 4H), 1.46-1.40 (m, 2H), 1.03(d, J=6.5 Hz, 6H).

Example 89

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-piperidin-4-ol

A solution of the product of Example 9 (175 mg), 4-hydroxypiperidine (79mg), and acetic acid (0.01 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (231 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (6% 2 M methanolicammonia/DCM) gave the title compound as a white crystalline solid (63mg). ¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz,2H), 3.99 (t, J=6.5 Hz, 2H), 3.71-3.62 (m,1H), 3.43 (s, 2H), 2.77-2.69(m, 2H), 2.49-2.34 (m, 6H), 2.15-2.05 (m, 2H), 2.01-1.92 (m, 2H),1.91-1.82 (m, 2H), 1.76 (br s,1H), 1.62-1.52 (m, 6H), 1.47-1.40 (m, 2H).

Example 90

1-Benzyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine

A solution of the product of Example 9 (175 mg), 1-benzylpiperazine(0.14 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated withsodium triacetoxyborohydride (210 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2% 2 M methanolicammonia/DCM) gave the title compound as a white solid (63 mg). ¹H NMR(400 MHz, CDCl₃): 7.32-7.17 (m, 7H), 6.83 (d, J=8.6 Hz, 2H), 3.98 (t,6.4 Hz, 2H), 3.50 (s, 2H), 3.44 (s, 2H), 2.52-2.35 (m, 14H), 2.00-1.92(m, 2H), 1.62-1.55 (m, 4H), 1.47-1.39 (m, 2H).

Example 91

1-Phenyl-4-[4-(3-piperidin-1-yl-propoxy)-benzyl]-piperazine

A solution of the product of Example 9 (175 mg), 1-phenylpiperazine(0.12 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated withsodium triacetoxyborohydride (210 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (2% 2 M methanolicammonia/DCM) gave the title compound as a white solid (70 mg). ¹H NMR(400 MHz, CDCl₃): 7.28-7.22 (m, 4H), 6.94-6.81 (m, 5H), 4.00 (t, J=6.5Hz, 2H), 3.50 (s, 2H), 3.21-3.16 (m, 4H), 2.61-2.56 (m, 4H), 2.50-2.35(m, 6H), 2.02-1.94 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.40 (m, 2H).

Example 92

Dibenzyl-(3-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrol-1-yl}-propyl)-amine

To a stirred suspension of sodium hydride (0.14 g) in DMF (9 mL) at RTwas added dropwise a solution of the product of Example 18 (1 g) in DMF(9 mL). After 20 min,1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane(0.876 mL) was added dropwise. After 20 min, the mixture was carefullytreated with water (30 mL) and then extracted several times withmethylene chloride. The combined organic layers were washed with brine,dried (sodium sulfate), filtered, and concentrated under reduced, givinga dark red oil (1.2 g). To a solution of this oil (0.211 g) indichloroethane (6 mL) was added benzaldehyde (0.138 mL), acetic acid(0.138 mL), and sodium triacetoxyborohydride (0.367 g). The mixture wasstirred for 12 h at RT and then diluted with methylene chloride andsaturated aqueous sodium bicarbonate solution. The organic layer wasseparated and the aqueous layer extracted with several portions ofmethylene chloride. The combined organic layers were washed with brine,dried (sodium sulfate), filtered and concentrated under reduced pressureto give an orange oil (0.289 g). Silica gel chromatography (2%methanol/ethyl acetate) afforded the title compound as a yellow oil(0.103 g). ¹H NMR (400 MHz, MeOH-d₄): 7.30-7.17 (m, 12H), 6.90-6.86 (m,2H), 6.58-6.57 (m, 1H), 6.01 (t, 3 Hz, 1H), 5.97-5.95 (m, 1H), 3.95 (t,J=6.3 Hz, 2H), 3.88 )t, J=7.6 Hz), 3.37 (s, 4H), 2.55-2.4 (m, 6H), 2.29(t, J=6.6 Hz, 2H), 2.02-1.95 (m, 2H), 1.75-1.68 (m, 2H), 1.66-1.58 (m,4H), 1.53-1.43 (m, 2H).

Example 93

1-{3-[4-(4-Benzyl-piperidin-1-ylmethyl)-phenoxy]-propyl}-piperidine

A solution of the product of Example 9 (175 mg), 4-benzylpiperidine(0.14 mL), and acetic acid (0.09 mL) in DCE (3 mL) was treated withsodium triacetoxyborohydride (210 mg). After 16 h, the resulting mixturewas treated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (1.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (97 mg). ¹H NMR(400 MHz, CDCl₃): 7.29-7.10 (m, 7H), 6.81 (d, J=8.3 Hz, 2H), 3.99 (t,J=6.3 Hz, 2H), 3.40 (s, 2H), 2.86-2.81 (m, 2H), 2.54-2.44 (m, 4H),2.00-1.81 (m, 4H), 1.65-1.40 (m, 13H), 1.35-1.23 (m, 2H).

Example 94

4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-morpholine

A solution of the product of Example 9 (175 mg), morpholine (0.07 mL),and acetic acid (0.09 mL) in DCE (3 mL) was treated with sodiumtriacetoxyborohydride (210 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (1 mL) and extracted with DCM (3×3mL). The combined organic phases were dried (magnesium sulfate) andevaporated. Chromatography of the residue (3.5% 2 M methanolicammonia/DCM) gave the title compound as a colorless oil (145 mg). ¹H NMR(400 MHz, CDCl₃): 7.21 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 3.99(t, J=6.4 Hz, 2H), 3.71-3.67 (m, 4H), 3.42 (s, 2H), 2.50-2.36 (m, 10H),2.01-1.93 (m, 2H), 1.63-1.56 (m, 4H), 1.49-1.40 (m, 2H).

Example 95

1-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-1,2,3,4-tetrahydro-quinoline

A solution of the product of Example 9 (175 mg),1,2,3,4-tetrahydro-quinoline (0.10 mL), and acetic acid (0.09 mL) in DCE(3 mL) was treated with sodium triacetoxyborohydride (210 mg). After 16h, the resulting mixture was treated with 10% sodium hydroxide (1 mL)and extracted with DCM (3×3 mL). The combined organic phases were dried(magnesium sulfate) and evaporated. Chromatography of the residue (1.5%2 M methanolic ammonia/DCM) gave the title compound as a colorless oil(77 mg). ¹H NMR (400 MHz, CDCl₃): 7.13 (d, J=8.8 Hz, 2H), 6.96 (t, J=7.3Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.58-6.51 (m, 2H), 4.40 (s, 2H), 3.97(t, J=6.3 Hz, 2H), 3.32 (dd, J=5.7, 5.7 Hz, 2H), 2.79 (t, J=6.3 Hz, 2H),2.50-2.35 (m, 6H), 2.02-1.92 (m, 4H), 1.62-1.55 (m, 4H), 1.47-1.39 (m,2H).

Example 96

1-(3-{4-[1-(3-Piperidin-1-yl-propyl)-1H-pyrrol-2-yl]-phenoxy}-propyl)-piperidine

To a stirred suspension of sodium hydride (0.051 g) in DMF (3 mL) at RTwas added dropwise the product of Example 18 (0.2 g) in DMF (4 mL).After 20 min, 1-(3-chloro-propyl)-piperdine (0.139 g) was added dropwiseand the mixture stirred for 12 h. The mixture was diluted with water andextracted several times with diethyl ether. The combined organic layerswere washed with brine, dried (sodium sulfate), filtered andconcentrated under reduced pressure, giving the title compound as a darkred oil (0.257 g). ¹H NMR (400 MHz, C₆D₆): 7.35 (d, J=8.8 Hz, 2H), 6.90(d, J=8.8 Hz, 2H), 6.72 (t, J=2.5 Hz, 1H), 6.44 (d, J=2.5 Hz), 3.82 (m,4H), 2.37-2.16 (m, 8H), 2.06 (br s, 4H), 1.96 (t, J=6.6 Hz, 2H),1.87-1.81 (m, 2H), 1.59-1.22 (m, 16H).

Example 97

Diethyl-[3-(4-piperidin-1-ylmethyl-phenoxy)-propyl]-amine

A suspension of the product of Example 17 (176 mg),3-diethylaminolpropan-1-ol (0.14 mL), and polymer-supportedtriphenylphosphine (613 mg, 3 mmol/g phosphorus content) indichloromethane (4 mL) was treated with a solution of di-tert-butylazodicarboxylate (318 mg) in dichloromethane (1 mL). The resultingmixture was stirred for 3 h and filtered. Chromatography of the filtrate(0-8% 2M methanolic ammonia/dichloromethane) gave the title compound asa pale yellow oil (130 mg). ¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz,2H), 6.82 (d, J=8.6 Hz, 2H), 3.98 (t, J=3.98 Hz, 2H), 3.42 (s, 2H),2.64-2.52 (m, 6H), 2.41-2.33 (m, 4H), 1.96-1.86 (m, 2H), 1.59-1.53 (m,4H), 1.44-1.38 (m, 2H).1.04 (t, J=7.2 Hz, 6H).

Example 98 Biological Methods In Vitro

Transfection of Cells with Human Histamine Receptor

A 10 cm tissue culture dish with a confluent monolayer of SK—N-MC cellswas split two days prior to transfection. Using sterile technique themedia was removed and the cells were detached from the dish by theaddition of trypsin. One fifth of the cells were then placed onto a new10 cm dish. Cells were grown in a 37° C. incubator with 5% CO₂ inMinimal Essential Media Eagle with 10% Fetal Bovine Serum. After twodays cells were approximately 80% confluent. These were removed from thedish with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One microgram of supercoiled H₃ receptor cDNA wasadded to the cells and mixed. The voltage for the electroporation wasset at 0.25 kV, the capacitance was set at 960 μF. After electroporationthe cells were diluted into 10 mL complete media and plated onto four 10cm dishes. Because of the variability in the efficiency ofelectroporation, four different concentrations of cells were plated. Theratios used were; 1:20, 1:10, 1:5, with the remainder of the cells beingadded to the fourth dish. The cells were allowed to recover for 24 hoursbefore adding the selection media (complete media with 600 μg/mL G418).After 10 days dishes were analyzed for surviving colonies of cells.Dishes with well isolated colonies were used. Cells from individualcolonies were isolated and tested. SK—N-MC cells were used because theygive efficient coupling for inhibition of adenylate cyclase. The clonesthat gave the most robust inhibition of adenylate cyclase in response tohistamine were used for further study.

[³H]-N-methylhistamine Binding

Cell pellets from histamine H₃ receptor-expressing SK—N-MC cells werehomogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatants from a 800 g spinwere collected, recentrifuged at 30,000 g for 30 minutes. Pellets werere-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes wereincubated with 0.8 nM [³H]-N-methylhistamine plus/minus test compoundsfor 45 min at 25° C. and harvested by rapid filtration over GF/C glassfiber filters (pretreated with 0.3% polyethylenimine) followed by fourwashes with ice cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine. ThepK_(i) values were calculated based on a K_(d) of 800 pM and a ligandconcentration ([L]) of 800 pM according to the formula:

K_(i)=(IC₅₀)/(1+([L]/(K_(d)))

In Vivo

Elucidation of oral absorption and blood-brain barrier penetrationprofiles of H₃ receptor antagonists in the rat

A rat in vivo system was used to determine the blood-brain barrierpenetration profiles and kinetics of various H₃ receptor antagonistsafter single bolus oral administration.

Female Sprague Dawley Rats (˜300 gram body weight) were housed inaccordance with institutional standards and allowed to acclimate for atleast 7 days prior to the study. Each H₃ antagonist was formulated in0.5% hydroxypropylmethyl cellulose at a concentration of 1 mg/mL fororal dosing. The test compound was administered to each of eight animalsas a single oral dose of 10 mL/kg (10 mg/kg). Remaining dosing solutionwas retained for analysis. Two animals from each original group of eightwere euthanized via CO₂ asphyxiation at t=1, 6, 24, and 48 hours. Aftereach animal was euthanized, 0.1 mL of its blood was sampled via cardiacpuncture, and its brain was removed via dissection of the cranial bonesand placed in a pre-weighed 50 mL conical tube on dry ice.

The blood was added to 0.3 mL of 6% trichloroacetic acid, and theacidified sample was vortexed and then centrifuged (5 minutes at 14,000rpm in a microcentrifuge). The clear supernatant was retained foranalysis. The frozen brain was weighed, homogenized in 6%trichloroacetic acid (3 mL/g wet weight of tissue), and thencentrifuged. The clear supernatant was retained for analysis. Thesupernatants from the blood and brain samples were analyzed by liquidchromatography with mass spectral detection utilizing selective reactionmonitoring (LC—MS/MS). The LC method used a Phenomonex Polar RP column(2×50 mm) and a linear solvent gradient of water and acetonitrile (both1% in acetic acid).

Graphs of H₃ receptor antagonist concentration versus time for blood andbrain were generated from the LC-MS/MS results. The mean residency time(MRT) of the H₃ receptor antagonist, in blood or in the brain, wascalculated from the ratio of the area under the first moment curve(AUMC) to the area under the concentration time curve (AUC): AUMC/AUC.The Blood Brain Barrier index was calculated from the log ofAUC_(brain)/AUC_(blood).

F. Other Embodiments

The features and advantages of the invention will be apparent to one ofordinary skill in view of the discussion, examples, embodiments, andclaims relating to the invention. The invention also contemplatesvariations and adaptations, based on the disclosure herein concerningthe key features and advantages of the invention, and within theabilities of one of ordinary skill.

1-53. (canceled)
 54. A method of treating dementia, mild cognitiveimpairment (pre-dementia), cognitive dysfunction, schizophrenia,depression manic disorders, bipolar disorders, and learning and memorydisorders in a subject, comprising administering an effective amount ofa compound of formula I to a subject in need of such treatment:

wherein R_(a) and R_(b) are independently C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈cycloakyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, or taken together with thenitrogen to which they are attached form a 4-7 membered heterocyclyloptionally including up to 3 additional heteroatoms; n is 0-4; one ofR₁, R₂ and R₃ is G, and the remaining two are hydrogen or halo; G is anitrogen-containing group selected from one of the following: —OL₁Q,-L₂Q, —N(L₁Q)R₅, -L₃C(L₁Q)R₆R₇, —C(L₁Q)R₆R₇,

wherein: L₁ is C₂₋₆ alkylene, C₃₋₈ cycloalkylene, C₄₋₆ alkenylene, C₄₋₆alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆alkylene, (C₂₋₅ heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, or(C₂₋₅ heteroaryoxy)C₁₋₆ alkylene; L₂ is C₁₋₆ alkylene, C₃₋₈cycloalkylene, C₃₋₆ alkenylene, C₃₋₆ alkynylene, C₂₋₅ alkanoyl,(phenyl)C₁₋₆ alkylene, (naphthylC₁₋₆ alkylene, (C₁₋₅ heteroaryl)C₁₋₆alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, or(C₁₋₅ heteroarylthio)C₁₋₆ alkylene; L₃ is C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene,phenyl, naphthyl, (naphthl)C₁₋₆ alkylene, C₁₋₅ heteroaryl)C₁₋₆ alkylene,(phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, or C₂₋₅heteroaryl; L₄ is C₁₋₅ alkylene; L₅is C₁₋₅ alkylene; L₆ is C₁₋₅alkylene; L₇ is C₁₋₅ alkylene or absent; Q is —NR₈R₉ or a non-aromaticC₂₋₁₅ heterocyclyl ring system containing at least one nitrogen atom andoptionally between 1 and 3 additional heteroatoms selected from O, S,and N in each ring; each of R₅ and R₆ is independently selected fromhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, and (C₂₋₇heterocyclyl)C₁₋₆ alkylene; R₇ is H, hydroxyl halo, C₂₋₆ alkoxy orabsent where the carbon linking L₆ and L₇ (or bonded to R₆) participatesin a double bond; each of R₈ and R₉ is independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, phenyl, (C₂₋₁₅heterocyclyl)C₁₋₆ alkylene, and (phenyl) C₁₋₆ alkylene; R₁₀ is H, C₁₋₈alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇ cycloalkyl)C₁₋₆ alkylene,(C₂₋₁₅ heterocyclyl)C₁₋₆ alkylene, or (phenyl) C₁₋₆ alkylene; whereineach of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl,alkynylene, heterocyclyl cycloalkyl and aryl groups may each beindependently and optionally substituted with between 1 and 3substituents selected from halo, amino, nitro, hydroxyl and C₁₋₃ alkyl;wherein substituents of Q can be further selected from carboxamide, C₂₋₆alkyl, C₁₋₈ heterocyclyl, N(C₁₋₆ alkyl)(C₁₋₈ heterocyclyl), NH(C₁₋₈heterocyclyl), (C₁₋₈ heterocyclyl) C₁₋₃ alkylene, O(C₁₋₈ heterocyclyl),C₁₋₆ alkoxy, (phenyl)C₃₋₆ cycloalkyl-O—, phenyl, (phenyl)C₁₋₃ alkylene,N(C₁₋₆ alkyl)[(phenyl)C₁₋₃ alkylene], and (phenyl)C₁₋₃ alkylene-O— whereeach of above heterocyclyl, phenyl, and alkyl groups may be optionallysubstituted with from 1 to 3 substituents independently selected fromhalogen, nitro, cyano, and C₁₋₃ alkyl; or a pharmaceutically acceptablesalt, ester, or amide thereof. 55-56. (canceled)
 57. The method of claim54 comprising (a) administering to a subject a jointly effective amountof a histamine H₁ receptor antagonist compound, and (b) administering tothe subject a jointly effective amount of a compound of claim 54, saidmethod providing a jointly therapeutically effective amount of saidcompounds.
 58. The method of claim 57 wherein the histamine H₁ receptorantagonist and the compound of claim 54, are present in the same dosageform.
 59. The method of claim 54 comprising (a) administering to thesubject a jointly effective amount of a histamine H₂ receptor antagonistcompound, and (b) administering to the subject a jointly effectiveamount of a compound of claim 54, said method providing a jointlytherapeutically effective amount of said compounds.
 60. The method ofclaim 59 wherein the histamine H₂ receptor antagonist and the compoundof claim 54, are present in the same dosage form. 61-65. (canceled) 66.The method of claim 54, wherein R_(a) and R_(b) taken together with thenitrogen to which they are attached form a 4-7 membered heterocyclyloptionally including up to 3 additional heteroatoms.
 67. The method ofclaim 54, wherein R₁ is hydrogen or halo, and one of R₂ and R₃ is G andthe other is hydrogen or halo.
 68. The method of claim 67, wherein R₂ isG.
 69. The method of claim 67, wherein R₃ is G.
 70. A method of treatingschizophrenia in a subject, comprising administering an effective amountof a compound of formula I to a subject in need of such treatment:

wherein R_(a) and R_(b) are independently C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, or taken together with thenitrogen to which they are attached form a 4-7 membered heterocyclyloptionally including up to 3 additional heteroatoms; n is 0-4; one ofR₁, R₂, and R₃ is G, and the remaining two are hydrogen or halo; G is anitrogen-containing group selected from one of the following: —OL₁Q,-L₂Q, —N(L₁Q)R₅, -L₃C(L₁Q)R₆R₇, —C(L₁Q)R₆R₇,

wherein: L₁ is C₂₋₆ alkylene, C₃₋₈ cycloalkylene, C₄₋₆ alkenylene, C₄₋₆alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆alkylene, (C₂₋₅ heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, or(C₂₋₅ heteroaryloxy)C₁₋₆ alkylene; L₂ is C₁₋₆ alkylene, C₃₋₈cycloalkylene, C₃₋₆ alkenylene, C₃₋₆ alkynylene, C₂₋₅ alkanoyl,(phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆ alkylene, (C₁₋₅ heteroaryl)C₁₋₆alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, or(C₁₋₅ heteroarylthio)C₁₋₆ alkylene; L₃ is C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene,phenyl, naphthyl, (naphthyl)C₁₋₆ alkylene, C₁₋₅ heteroaryl)C₁₋₆alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, orC₂₋₅ heteroaryl; L₄ is C₁₋₅ alkylene; L₅ is C₁₋₅ alkylene; L₆ is C₁₋₅alkylene; L₇ is C₁₋₅ alkylene or absent; Q is —NR₈R₉ or a non-aromaticC₂₋₁₅ heterocyclyl ring system containing at least one nitrogen atom andoptionally between 1 and 3 additional heteroatoms selected from O, S,and N in each ring; each of R₅ and R₆ is independently selected fromhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, and (C₂₋₇heterocyclyl)C₁₋₆ alkylene; R₇ is H, hydroxyl, halo, C₂₋₆ alkoxy orabsent where the carbon linking L₆ and L₇ (or bonded to R₆) participatesin a double bond; each of R₈ and R₉ is independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, phenyl, (C₂₋₁₅heterocyclyl)C₁₋₆ alkylene, and (phenyl) C₁₋₆ alkylene; R₁₀ is H, C₁₋₈alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇ cycloalkyl)C₁₋₆ alkylene,(C₂₋₁₅ heterocyclyl)C₁₋₆ alkylene, or (phenyl) C₁₋₆ alkylene; whereineach of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl,alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each beindependently and optionally substituted with between 1 and 3substituents selected from halo, amino, nitro, hydroxyl, and C₁₋₃ alkyl;wherein substituents of Q can be further selected from carboxamide, C₂₋₆alkyl, C₁₋₈ heterocyclyl, N(C₁₋₆ alkyl)(C₁₋₈ heterocyclyl), NH(C₁₋₈heterocyclyl), (C₁₋₈ heterocyclyl) C₁₋₃ alkylene, O(C₁₋₈ heterocyclyl),C₁₋₆ alkoxy, (phenyl)C₃₋₆ cycloalkyl-O—, phenyl, (phenyl) C₁₋₃ alkylene,N(C₁₋₆ alkyl)[(phenyl)C₁₋₃ alkylene], and (phenyl)C₁₋₃ alkylene-O— whereeach of above heterocyclyl, phenyl, and alkyl groups may be optionallysubstituted with from 1 to 3 substituents independently selected fromhalogen, nitro, cyano, and C₁₋₃ alkyl; or a pharmaceutically acceptablesalt, ester, or amide thereof.
 71. The method of claim 70, wherein R_(a)and R_(b) taken together with the nitrogen to which they are attachedform a 4-7 membered heterocyclyl optionally including up to 3 additionalheteroatoms.
 72. The method of claim 70, wherein R₁ is hydrogen or halo,and one of R₂ and R₃ is G and the other is hydrogen or halo.
 73. Themethod of claim 72, wherein R₂ is G.
 74. The method of claim 72, whereinR₃ is G.
 75. A method of treating depression in a subject, comprisingadministering an effective amount of a compound of formula I to asubject in need of such treatment:

wherein R_(a) and R_(b) are independently C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, or taken together with thenitrogen to which they are attached form a 4-7 membered heterocyclyloptionally including up to 3 additional heteroatoms; n is 0-4; one ofR₁, R₂, and R₃ is G, and the remaining two are hydrogen or halo; G is anitrogen-containing group selected from one of the following: —OL₁Q,-L₂Q, —N(L₁Q)R₅, -L₃C(L₁Q)R₆R₇, —C(L₁Q)R₆R₇,

wherein: L₁ is C₂₋₆ alkylene, C₃₋₈ cycloalkylene, C₄₋₆ alkenylene, C₄₋₆alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆alkylene, (C₂₋₅ heteroaryl)C₁₋₆ alkylene, (phenoxy)C₁₋₆ alkylene, or(C₂₋₅ heteroaryloxy)C₁₋₆ alkylene; L₂ is C₁₋₆ alkylene, C₃₋₈cycloalkylene, C₃₋₆ alkenylene, C₃₋₆ alkynylene, C₂₋₅ alkanoyl,(phenyl)C₁₋₆ alkylene, (naphthyl)C₁₋₆ alkylene, (C₁₋₅ heteroaryl)C₁₋₆alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, or(C₁₋₅ heteroarylthio)C₁₋₆ alkylene; L₃ is C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₂₋₅ alkanoyl, (phenyl)C₁₋₆ alkylene,phenyl, naphthyl, (naphthyl)C₁₋₆ alkylene, C₁₋₅ heteroaryl)C₁₋₆alkylene, (phenoxy)C₁₋₆ alkylene, (C₁₋₅ heteroaryloxy)C₁₋₆ alkylene, orC₂₋₅ heteroaryl; L₄ is C₁₋₅ alkylene; L₅ is C₁₋₅ alkylene; L₆ is C₁₋₅alkylene; L₇ is C₁₋₅ alkylene or absent; Q is —NR₈R₉ or a non-aromaticC₂₋₁₅ heterocyclyl ring system containing at least one nitrogen atom andoptionally between 1 and 3 additional heteroatoms selected from O, S,and N in each ring; each of R₅ and R₆ is independently selected fromhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, and (C₂₋₇heterocyclyl)C₁₋₆ alkylene; R₇ is H, hydroxyl, halo, C₂₋₆ alkoxy orabsent where the carbon linking L₆ and L₇ (or bonded to R₆) participatesin a double bond; each of R₈ and R₉ is independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇cycloalkyl)C₁₋₆ alkylene, C₂₋₁₅ heterocyclyl, phenyl, (C₂₋₁₅heterocyclyl)C₁₋₆ alkylene, and (phenyl) C₁₋₆ alkylene; R₁₀ is H, C₁₋₈alkyl, C₃₋₈ alkenyl, C₃₋₇ cycloalkyl, (C₃₋₇ cycloalkyl)C₁₋₆ alkylene,(C₂₋₁₅ heterocyclyl)C₁₋₆ alkylene, or (phenyl) C₁₋₆ alkylene; whereineach of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl,alkynylene, heterocyclyl, cycloalkyl, and aryl groups may each beindependently and optionally substituted with between 1 and 3substituents selected from halo, amino, nitro, hydroxyl, and C₁₋₃ alkyl;wherein substituents of Q can be further selected from carboxamide, C₂₋₆alkyl, C₁₋₈ heterocyclyl, N(C₁₋₆ alkyl)(C₁₋₈ heterocyclyl), NH(C₁₋₈heterocyclyl), (C₁₋₈ heterocyclyl) C₁₋₃ alkylene, O(C₁₋₈ heterocyclyl),C₁₋₆ alkoxy, (phenyl)C₃₋₆ cycloalkyl-O—, phenyl, (phenyl) C₁₋₃ alkylene,N(C₁₋₆ alkyl)[(phenyl)C₁₋₃ alkylene], and (phenyl)C₁₋₃ alkylene-O— whereeach of above heterocyclyl, phenyl, and alkyl groups may be optionallysubstituted with from 1 to 3 substituents independently selected fromhalogen, nitro, cyano, and C₁₋₃ alkyl; or a pharmaceutically acceptablesalt, ester, or amide thereof.
 76. The method of claim 75, wherein R_(a)and R_(b) taken together with the nitrogen to which they are attachedform a 4-7 membered heterocyclyl optionally including up to 3 additionalheteroatoms.
 77. The method of claim 75, wherein R₁ is hydrogen or halo,and one of R₂ and R₃ is G and the other is hydrogen or halo.
 78. Themethod of claim 77, wherein R₂ is G.
 79. The method of claim 77, whereinR₃ is G.